40-o-(2-hydroxy)ethyl-rapamycin coated stent

ABSTRACT

A method and coating for reducing the release rate of an active agent from an implantable device, such as a stent, is disclosed.

BACKGROUND OF THE INVENTION

Field of the Invention

The invention relates to drug eluting implantable devices, one exampleof which is a stent. More particularly, the invention relates tosustained delivery of 40-O-(2-hydroxy)ethyl-rapamycin from a stent.

Description of the Background

Percutaneous transluminal coronary angioplasty (PTCA) is a procedure fortreating heart disease. A catheter assembly having a balloon portion isintroduced percutaneously into the cardiovascular system of a patientvia the brachial or femoral artery. The catheter assembly is advancedthrough the coronary vasculature until the balloon portion is positionedacross the occlusive lesion. Once in position across the lesion, theballoon is inflated to a predetermined size to remodel the vessel wall.The balloon is then deflated to a smaller profile to allow the catheterto be withdrawn from the patient's vasculature.

A problem associated with the above procedure includes formation ofintimal flaps or torn arterial linings, which can collapse and occludethe conduit after the balloon is deflated. Vasospasms and recoil of thevessel wall also threaten vessel closure. Moreover, thrombosis andrestenosis of the artery may develop over several months after theprocedure, which may necessitate another angioplasty procedure or asurgical by-pass operation. To reduce the partial or total occlusion ofthe artery by the collapse of arterial lining and to reduce the chanceof the development of thrombosis and restenosis, an expandable,intraluminal prosthesis, also known as a stent, is implanted in thelumen to maintain the vascular patency.

Stents act as scaffoldings, functioning to physically hold open and, ifdesired, to expand the wall of the passageway. Typically, stents arecapable of being compressed so that they can be inserted through smalllumens via catheters and then expanded to a larger diameter once theyare at the desired location. Mechanical intervention via stents hasreduced the rate of restenosis as compared to balloon angioplasty. Yet,restenosis is still a significant clinical problem with rates rangingfrom 20-40%. When restenosis does occur in the stented segment, itstreatment can be challenging, as clinical options are more limited ascompared to lesions that were treated solely with a balloon.

Stents are used not only for mechanical intervention but also asvehicles for providing biological therapy. Biological therapy can beachieved by medicating the stents. Medicated stents provide for thelocal administration of a therapeutic substance at the diseased site. Inorder to provide an efficacious concentration to the treated site,systemic administration of such medication often produces adverse oreven toxic side effects for the patient. Local delivery is a preferredmethod of treatment in that smaller total levels of medication areadministered in comparison to systemic dosages, but are concentrated ata specific site. Local delivery thus produces fewer side effects andachieves more favorable results.

One proposed method of medicating stents involves the use of a polymericcarrier coated onto the surface of the stent. A composition including asolvent, a polymer dissolved in the solvent, and a therapeutic substancedispersed in the blend is applied to the stent by immersing the stent inthe composition or by spraying the composition onto the stent. Thesolvent is allowed to evaporate, leaving on the stent strut surfaces acoating of the polymer and the therapeutic substance impregnated in thepolymer.

A potential shortcoming of the foregoing method of medicating stents isthat the release rate of the therapeutic substance may be too high toprovide an efficacious treatment. This shortcoming may be especiallypronounced with certain therapeutic substances. For instance, it hasbeen found that the release rate of 40-O-(2-hydroxy)ethyl-rapamycin froma standard polymeric coating is greater than 50% in about 24 hours.Thus, there is a need for a coating that reduces the release rate of40-O-(2-hydroxy)ethyl-rapamycin in order to provide a more efficaciousrelease rate profile. The present invention provides a coating to meetthis need.

SUMMARY

In accordance with one aspect of the invention, a stent is disclosedincluding a radially expandable body and a coating covering at least aportion of the body, the coating having 40-O-(2-hydroxy)ethyl-rapamycin,or an analog or derivative thereof, wherein the release rate of the40-O-(2-hydroxy)ethyl-rapamycin, or the analog or derivative thereof, in24 hours after the implantation of the stent is less than about 50% ofthe total amount contained in the coating.

In accordance with a further aspect of the present invention, a methodof inhibiting or eliminating the development of restenosis following astent placement procedure is disclosed including implanting a stentwhich can elude 40-O-(2-hydroxy)ethyl-rapamycin, or an analog orderivative thereof, at a release rate of less than 50% of the totalamount of the drug carried by the stent in a 24 hour period followingthe implantation procedure.

In a further aspect, a method of providing drug delivery capability fora stent is disclosed including coating a stent with a polymer containing40-O-(2-hydroxy)ethyl-rapamycin, or analog or derivative thereof,wherein the coating has an in vivo release rate of less than 50% of thetotal amount of the 40-O-(2-hydroxy)ethyl-rapamycin, or analog orderivative thereof, in a 24 hour period.

In yet another aspect of the present invention, a method of treating apolymeric coating on a stent to reduce the rate of release of the drugfrom the coating is disclosed including exposing the coating to atemperature of a sufficient degree to cause modifications in thestructure of the polymer which allows for the reduction of the releaserate of the drug through the polymer.

Also disclosed, in another aspect, is a method of treating a coatedstent containing a therapeutic substance to reduce the rate of releaseof the therapeutic substance from the coating including subjecting thecoating to a stimuli so as to change the property of at least a regionof the coating such that the change of the property of the region of thecoating causes the therapeutic substance to be released more slowly fromthe region that has the changed property.

In another aspect of the present invention, a method of preparing acoated stent containing 40-O-(2-hydroxy)ethyl-rapamycin, or analog orderivative thereof, for an implantation procedure is disclosed includingsterilizing the stent while maintaining the peak purity of the40-O-(2-hydroxy)ethyl-rapamycin, or analog or derivative thereof, at alevel greater than 90%.

BRIEF DESCRIPTION OF THE FIGURES

FIGS. 1A-1C illustrate coatings deposited over an implantable medicalsubstrate in accordance with various embodiments of the presentinvention;

FIGS. 2-3 are graphs showing the release rate of40-O-(2-hydroxy)ethyl-rapamycin from stent coatings in accordance withembodiments of the present invention;

FIG. 4 is a chromatograph as referred to in Examples 32 and 33; and

FIG. 5 is a graph showing the release rate of40-O-(2-hydroxy)ethyl-rapamycin from stent coatings in accordance withan embodiment of the present invention.

DETAILED DESCRIPTION Forming an Active Ingredient-Containing Coating

Herein is disclosed a method of forming a coating for an implantabledevice including applying a first composition with40-O-(2-hydroxy)ethyl-rapamycin, or a functional analog or structuralderivative thereof, to at least a portion of an implantable device toform a first layer. The release rate of 40-O-(2-hydroxy)ethyl-rapamycinis advantageously controlled by various methods and coatings asdescribed below. In particular, by using the methods and coatings of thepresent invention, the release rate of the40-O-(2-hydroxy)ethyl-rapamycin, or analog or derivative thereof, can beless than about 50% in 24 hours.

40-O-(2-hydroxy)ethyl-rapamycin is an immunosuppressant which is underinvestigation primarily for use with cyclosporine/steroids to preventacute rejection episodes in renal transplant recipients.40-O-(2-hydroxy)ethyl-rapamycin is also under investigation forrejection prophylaxis following other types of transplantation (e.g.,lung, liver). The chemical structure for 40-O-(2-hydroxy)ethyl-rapamycinis as follows:

Examples of analogs or derivatives of 40-O-(2-hydroxy)ethyl-rapamycininclude but are not limited to 40-O-(3-hydroxy)propyl-rapamycin and40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin.

40-O-(2-hydroxy)ethyl-rapamycin binds to the cytosolic immunophyllinFKBP12 and inhibits growth factor-driven cell proliferation, includingthat of T-cells and vascular smooth muscle cells. The actions of40-O-(2-hydroxy)ethyl-rapamycin occur late in the cell cycle (i.e., lateG1 stage) compared to other immunosuppressive agents such as tacrolimusor cyclosporin which block transcriptional activation of earlyT-cell-specific genes. Since 40-O-(2-hydroxy)ethyl-rapamycin can act asa potent anti-proliferative agent, it is believed that40-O-(2-hydroxy)ethyl-rapamycin can be an effective agent to treatrestenosis by being delivered to a local treatment site from a polymericcoated implantable device such as a stent.

The composition including 40-O-(2-hydroxy)ethyl-rapamycin can be appliedto the implantable device in various ways. In one embodiment, a firstlayer can be formed on the implantable device by (1) immersing theimplantable device into a solution containing40-O-(2-hydroxy)ethyl-rapamycin dissolved in a suitable solvent, or (2)spray coating the implantable device with the same solution containing40-O-(2-hydroxy)ethyl-rapamycin to form a reservoir layer. In thisembodiment, the implantable device can include cavities or micro-poresfor containing the 40-O-(2-hydroxy)ethyl-rapamycin.

The 40-O-(2-hydroxy)ethyl-rapamycin can also be blended with a polymerand applied to the implantable device to form the reservoir layer.“Polymer,” “poly” and “polymeric” are defined as compounds that are theproduct of a polymerization reaction and are inclusive of homopolymers,copolymers, terpolymers etc., including random, alternating, block, andgraft variations thereof. The polymers should have a high capacity ofadherence to the surface of an implantable device, such as a metallicsurface of a stent, and a high capacity of adherence to polymericsurfaces.

In accordance with one embodiment, when the40-O-(2-hydroxy)ethyl-rapamycin is blended with a polymer for thereservoir layer, the ratio of 40-O-(2-hydroxy)ethyl-rapamycin, or analogor derivative thereof, to polymer by weight in the reservoir layer isabout 1:2.8 to about 1:1. It has been found that this particular rangeof 40-O-(2-hydroxy)ethyl-rapamycin:polymer ratio provides a beneficialrelease rate of the 40-O-(2-hydroxy)ethyl-rapamycin from the polymermatrix.

In accordance with another embodiment, when the40-O-(2-hydroxy)ethyl-rapamycin is blended with a polymer for thereservoir layer, the 40-O-(2-hydroxy)ethyl-rapamycin, or analog orderivative thereof, is in the amount of about 50 μg to about 500 μg,more narrowly about 90 μg to about 350 μg, and the polymer is in theamount of about 50 μg to about 1000 μg, more narrowly about 90 μg toabout 500 μg. These particular ranges of amounts for40-O-(2-hydroxy)ethyl-rapamycin and a polymer can provide a beneficialrelease rate of the 40-O-(2-hydroxy)ethyl-rapamycin from the polymermatrix.

When the polymer solution is being prepared, a predetermined amount of apolymer can be added to a predetermined amount of a compatible solvent.“Solvent” is defined as a liquid substance or composition that iscompatible with the components of the composition and is capable ofdissolving the component(s) at the concentration desired in thecomposition. Representative examples of solvents include chloroform,acetone, water (buffered saline), dimethylsulfoxide (DMSO), propyleneglycol methyl ether (PM,) iso-propylalcohol (IPA), n-propylalcohol,methanol, ethanol, tetrahydrofuran (THF), dimethylformamide (DMF),dimethylacetamide (DMAC), benzene, toluene, xylene, hexane, cyclohexane,pentane, heptane, octane, nonane, decane, decalin, ethyl acetate, butylacetate, isobutyl acetate, isopropyl acetate, butanol, diacetonealcohol, benzyl alcohol, 2-butanone, cyclohexanone, dioxane, methylenechloride, carbon tetrachloride, tetrachloroethylene, tetrachloro ethane,chlorobenzene, 1,1,1-trichloroethane, formamide, hexafluoroisopropanol,1,1,1-trifluoroethanol, and hexamethyl phosphoramide and a combinationthereof.

The polymer can be added to the solvent at ambient pressure and underanhydrous atmosphere. If necessary, gentle heating and stirring and/ormixing can be employed to effect dissolution of the polymer into thesolvent, for example 12 hours in a water bath at about 60° C.

Sufficient amounts of 40-O-(2-hydroxy)ethyl-rapamycin can then bedispersed in the blended composition of the polymer and the solvent. Thepolymer can comprise from about 0.1% to about 35%, more narrowly fromabout 0.5% to about 20% by weight of the total weight of thecomposition, the solvent can comprise from about 59.9% to about 99.8%,more narrowly from about 79% to about 99% by weight of the total weightof the composition, and the 40-O-(2-hydroxy)ethyl-rapamycin can comprisefrom about 0.1% to about 40%, more narrowly from about 1% to about 9% byweight of the total weight of the composition. More than 9% by weight ofthe 40-O-(2-hydroxy)ethyl-rapamycin could adversely affectcharacteristics that are desirable in the polymeric coating, such asadhesion of the coating to the device. With the use of the optionalprimer layer, weight ratios of more than 9% for the active ingredientare achievable without compromising the effectiveness of the adhesion.Selection of a specific weight ratio of the polymer and solvent isdependent on factors such as, but not limited to, the material fromwhich the device is made, the geometrical structure of the device, andthe type and amount of the active ingredient employed.

Optionally, a second solvent, such as tefrahydrofuran (THF) ordimethylformamide (DMF), can be used to improve the solubility of the40-O-(2-hydroxy)ethyl-rapamycin in the composition. The second solventcan be added to the composition or the 40-O-2-hydroxy)ethyl-rapamycincan be added to the second solvent prior to mixture with the blend.

The 40-O-(2-hydroxy)ethyl-rapamycin should be in true solution orsaturated in the blended composition. If the40-O-(2-hydroxy)ethyl-rapamycin is not completely soluble in thecomposition, operations including mixing, stirring, and/or agitation canbe employed to effect homogeneity of the residues. The40-O-(2-hydroxy)ethyl-rapamycin can also be first added to the secondsolvent prior to admixing with the composition. The40-O-(2-hydroxy)ethyl-rapamycin may be added so that the dispersion isin fine particles.

Representative examples of polymers that can be combined with40-O-(2-hydroxy)ethyl-rapamycin for the reservoir layer include ethylenevinyl alcohol copolymer (commonly known by the generic name EVOH or bythe trade name EVAL), poly(hydroxyvalerate); poly(L-lactic acid);polycaprolactone; poly(lactide-co-glycolide); poly(hydroxybutyrate);poly(hydroxybutyrate-co-valerate); polydioxanone; polyorthoester;polyanhydride; poly(glycolic acid); poly(D,L-lactic acid); poly(glycolicacid-co-trimethylene carbonate); polyphosphoester; polyphosphoesterurethane; poly(amino acids); cyanoacrylatcs; poly(trimethylenecarbonate); poly(iminocarbonate); copoly(ether-esters) (e.g. PEO/PLA);polyalkylene oxalates; polyphosphazenes; biomolecules, such as fibrin,fibrinogen, cellulose, starch, collagen and hyaluronic acid;polyurethanes; silicones; polyesters; polyolefins; polyisobutylene andethylene-alphaolefin copolymers; acrylic polymers and copolymers; vinylhalide polymers and copolymers, such as polyvinyl chloride; polyvinylethers, such as polyvinyl methyl ether; polyvinylidene halides, such aspolyvinylidene fluoride and polyvinylidene chloride; polyacrylonitrile;polyvinyl ketones; polyvinyl aromatics, such as polystyrene; polyvinylesters, such as polyvinyl acetate; copolymers of vinyl monomers witheach other and olefins, such as ethylene-methyl methacrylate copolymers,acrytonitrile-styrene copolymers, ABS resins, and ethylene-vinyl acetatecopolymers; polyamides, such as Nylon 66 and polycaprolactam; alkydresins; polycarbonates; polyoxymethylenes; polyamides; polyethers; epoxyresins; polyurethanes; rayon; rayon-triacetate; cellulose acetate;cellulose butyrate; cellulose acetate butyrate; cellophane; cellulosenitrate; cellulose propionate; cellulose ethers; and carboxymethylcellulose.

Ethylene vinyl alcohol is functionally a very suitable choice ofpolymer. Ethylene vinyl alcohol copolymer refers to copolymerscomprising residues of both ethylene and vinyl alcohol monomers. One ofordinary skill in the art understands that ethylene vinyl alcoholcopolymer may also be a terpolymer so as to include small amounts ofadditional monomers, for example less than about five (5) molepercentage of styrenes, propylene, or other suitable monomers. Ethylenevinyl alcohol copolymers ate available commercially from companies suchas Aldrich Chemical Company, Milwaukee, Wis., or EVAL Company ofAmerica, Lisle, Ill., or can be prepared by conventional polymerizationprocedures that are well known to one of ordinary skill in the art.

The copolymer of EVAL allows for good control capabilities of therelease rate of the 40-O-(2-hydroxy)ethyl-rapamycin. As a general rule,an increase in she amount of the ethylene comonomer content decreasesthe rate that the 40-O-(2-hydroxy)ethyl-rapamycin is released from thecopolymer matrix. The release rate of the40-O-(2-hydroxy)ethyl-rapamycin typically decreases as thehydrophilicity of the copolymer decreases. An increase in the amount ofthe ethylene comonomer content increases the overall hydrophobicity ofthe copolymer, especially as the content of vinyl alcohol isconcomitantly reduced. It is also thought that the release rate and thecumulative amount of the active ingredient that is released is directlyproportional to the total initial content of the ingredient in thecopolymer matrix. Accordingly, a wide spectrum of release rates can beachieved by modifying the ethylene comonomer content and the initialamount of the 40-O-(2-hydroxy)ethyl-rapamycin.

Besides 40-O-(2-hydroxy)ethyl-rapamycin, another active agent can alsobe added to the first composition. The additional active agent may beany substance capable of exerting a therapeutic or prophylactic effectin the practice of the present invention. Examples of such active agentsinclude antiproliferative, antineoplastic, antiinflammatory,antiplatelet, anticoagulant, antifibrin, antithrombin, antimitotic,antibiotic, and antioxidant substances as well as combinations thereof.A suitable example of an antiproliferative substance is actinomycin D,or derivatives and analogs thereof (manufactured by Sigma-Aldrich 1001West Saint Paul Avenue, Milwaukee, Wis. 53233; or COSMEGEN availablefrom Merck). Synonyms of actinomycin D include dactinomycin, actinomycinIV, actinomycin I₁, actinomycin X₁, and actinomycin C₁. Examples ofsuitable antineoplastics include paclitaxel and docetaxel. Examples ofsuitable antiplatelets, anticoagulants, antifibrins, and antithrombinsinclude aspirin, sodium heparin, low molecular weight heparin, hirudin,argatroban, forskolin, vapiprost, prostacyclin and prostacyclin analogs,dextran, D-phe-pro-arg-chloromethylketone (synthetic antithrombin),dipyridamole, glycoprotein IIb/IIIa platelet membrane receptorantagonist, recombinant hirudin, thrombin inhibitor (available fromBiogen), and 7E-3B® (an antiplatelet drug from Centocor). Examples ofsuitable antimitotic agents include methotrexate, azathioprine,vincristine, vinblastine, fluorouracil, adriamycin, and mutamycin.Examples of suitable cytostatic or antiproliferative agents includeangiopeptin (a somatostatin analog from Ibsen), angiotensin convertingenzyme inhibitors such as CAPTOPRIL, (available from Squibb), CILAZAPRIL(available from Hoffman-LaRoche), or LISINOPRIL (available from Merck &Co., Whitehouse Station, N.J.); calcium channel blockers (such asNifedipine), colchicine, fibroblast growth factor (FGF) antagonists,histamine antagonist, LOVASTATIN (an inhibitor of HMG-CoA reductase, acholesterol lowering drug from Merck & Co.), monoclonal antibodies (suchas PDGF receptors), nitroprusside, phosphodiesterase inhibitors,prostaglandin inhibitor (available form Glazo), Seramin (a PDGFantagonist), serotonin blockers, thioprotease inhibitors,triazolopyrimidine (a PDGF antagonist), and nitric oxide. Othertherapeutic substances or agents that may be appropriate includealpha-interferon; genetically engineered epithelial cells;dexamethasone; rapamycin; estradiol; clobetasol propionate; cisplatin;insulin sensitizers; receptor tyrosine kinase inhibitors; andcarboplatin. Exposure of the composition to the active ingredient shouldnot adversely alter the active ingredient's composition orcharacteristic. Accordingly, the particular active ingredient isselected for compatibility with the blended composition.

The dosage or concentration of 40-O-(2-hydroxy)ethyl-rapamycin or otheractive agent required to produce a therapeutic effect should be lessthan the level at which the 40-O-(2-hydroxy)ethyl-rapamycin or otheractive agent produces unwanted toxic effects and greater than the levelat which non-therapeutic results are obtained. The dosage orconcentration of 40-O-(2-hydroxy)ethyl-rapamycin or other active agentrequired to inhibit the desired cellular activity of the vascularregion, for example, can depend upon factors such as the particularcircumstances of the patient; the nature of live trauma; the nature ofthe therapy desired; the time over which the ingredient administeredresides at the vascular site; and if other bioactive substances areemployed, the nature and type of the substance or combination ofsubstances. Therapeutically effective dosages can be determinedempirically, for example by infusing vessels from suitable animal modelsystems and using immunohistochemical, fluorescent or electronmicroscopy methods to detect the agent and its effects, or by conductingsuitable in vitro studies. Standard pharmacological test procedures todetermine dosages are understood by one of ordinary skill in the art.

Forming a Barrier Layer to Reduce the Rate of Release

In some coatings, the release rate of the40-O-(2-hydroxy)ethyl-rapamycin may be too high to be clinically useful.For example, in Example 22 below, the percentage of40-O-(2-hydroxy)ethyl-rapamycin in released from a stent coating withouta barrier layer in 24 hours was determined to be 58.55 as measured in aporcine serum release rate procedure. The release rate from the coatingof Example 22 may be too high for a treatment using40-O-(2-hydroxy)ethyl-rapamycin as the active agent. The barrier layerof the present invention can reduce the rate of release or delay thetime at which the 40-O-(2-hydroxy)ethyl-rapamycin is released from thereservoir layer.

In accordance with one embodiment, the barrier layer can be applied on aselected region of the reservoir layer to form a rate reducing member.The composition for the barrier layer can be substantially free ofactive agents. Alternatively, for maximum blood compatibility, compoundssuch as polyethylene glycol, heparin, heparin derivatives havinghydrophobic counterions, or polyethylene oxide can be added to thebarrier layer.

The choice of polymer for the barrier layer can be the same as theselected polymer for the reservoir. The use of the same polymer, asdescribed for some of the embodiments, significantly reduces oreliminates any interfacial incompatibilities, such as lack of adhesion,which may exist in the employment of two different polymeric layers.

Representative examples of polymers that can be used for a barrier layercan include polytetrafluoroethylene, perfluoro elastomers,ethylene-tetrafluoroethylene copolymer, fluoroethylene-alkyl vinyl ethercopolymer, polyhexafluoropropylene, low density linear polyethyleneshaving high molecular weights, ethylene-olefin copolymers, atacticpolypropylene, polyisobutene, polybutylenes, polybutenes,styrene-ethylene-styrene block copolymers, styrene-butylene-styreneblock copolymers, styrene-butadiene-styrene block copolymers, andethylene methacrylic acid copolymers of low methacrylic acid content.

Ethylene vinyl alcohol is functionally a very suitable choice ofpolymer. The copolymer allows for good control capabilities over therelease rate of the 40-O-(2-hydroxy)ethyl-rapamycin. As a general rule,an increase in the amount of the ethylene comonomer content decreasesthe rate that the 40-O-(2-hydroxy)ethyl-rapamycin is released from thecopolymer matrix. The release rate of the40-O-(2-hydroxy)ethyl-rapamycin decreases as the hydrophilicity of thepolymer decreases. An increase in the amount of the ethylene comonomercontent increases the overall hydrophobicity of the copolymer,especially as the content of vinyl alcohol is concomitantly reduced.

Fluoropolymers are also a suitable choice for the barrier layercomposition. For example, polyvinylidene fluoride (otherwise known asKYNAR, available from ATOFINA Chemicals, Philadelphia, Pa.) can bedissolved in HFE FLUX REMOVER (Techspray, Amarillo, Tex.) and canoptionally be combined with EVAL to form the barrier layer composition.Also, solution processing of fluoropolymers is possible, particularlythe low crystallinity varieties such as CYTOP available from Asahi Glassand TEFLON AF available from DuPont. Solutions of up to about 15%(wt/wt) are possible in perfluoro solvents, such as FC-75 (availablefrom 3M under the brand name FLUORINERT), which are non-polar, lowboiling solvents. Such volatility allows the solvent to be easily andquickly evaporated following the application of the polymer-solventsolution to the implantable device.

In one embodiment, polybutylmethacrylate can be used for the barrierlayer. Polybutylmethacrylate, for example, can be dissolved in asolution of xylene, acetone and HFE FLUX REMOVER.

The barrier layer can also be styrene-ethylene/butylene-styrene blockcopolymer. Styrene-ethylene/butylene-styrene block copolymer, e.g.,Kraton G-series, can be dissolved in non-polar solvents such as, but notlimited to, toluene, xylene, and decalin.

Other choices of polymers for the rate-limiting membrane include, butare not limited to, ethylene-anhydride copolymers; ethylene vinylacetate copolymers having, for example, a mol % of vinyl acetate of fromabout 9% to about 25%; and ethylene-acrylic acid copolymers having, forexample, a mol % of acrylic acid of from about 2% to about 25%. Theethylene-anhydride copolymer available from Bynel adheres well to EVALand thus would function well as a barrier layer over a reservoir layermade from EVAL. The copolymer can be dissolved in organic solvents, suchas dimethylsulfoxide and dimethylacetamide. Ethylene vinyl acetatepolymers can be dissolved in organic solvents, such as toluene andn-butyl acetate. Ethylene-acrylic acid copolymers can be dissolved inorganic solvents, such as methanol, isopropyl alcohol, anddimethylsulfoxide.

Yet another choice of polymer for the rate-limiting membrane is across-linked silicone elastomer. Loose silicone and silicone with verylow cross-linking are thought to cause an inflammatory biologicalresponse. However, it is believed that a thoroughly cross-linkedsilicone elastomer, having low levels of leachable silicone polymer andoligomer, is an essentially non-inflammatory substance. Siliconeelastomers, such as Nusil MED-4750, MED-4755, or MED2-6640, having hightensile strengths, for example between 1200 psi and 1500 psi, willlikely have the best durability during crimping, delivery, and expansionof a stent as well as good adhesion to a reservoir layer, e.g., EVAL orthe surface of an implantable device.

The embodiments of the composition for a rate-reducing membrane ordiffusion barrier layer are prepared by methods wherein all componentsare combined, then blended. More particularly, a predetermined amount ofa polymer can be added to a predetermined amount of a compatiblesolvent. The selected solvent should be capable of placing the polymerinto solution at the concentration desired.

The polymer can be added to the solvent at ambient pressure and underanhydrous atmosphere. If necessary, gentle heating and stirring and/ormixing can be employed to effect dissolution of the polymer into thesolvent, for example 12 hours in a water bath at about 60° C. Thepolymer can comprise from about 0.1% to about 35%, more narrowly fromabout 1% to about 20% by weight of the total weight of the composition,and the solvent can comprise from about 65% to about 99.9%, morenarrowly from about 80% to about 98% by weight of the total weight ofthe composition. Selection of a specific weight ratio of the polymer andsolvent is dependent on factors such as, but not limited to, the type ofpolymer and solvent employed, the type of underlying reservoir layer,and the method of application.

In an embodiment, the barrier layer contains a polymer in the amount ofabout 25 μg to about 500 μg, more narrowly about 65 μg to about 350 μg.This particular range for the amount of barrier polymer can provide abeneficial release rate of the 40-O-(2-hydroxy)ethyl-rapamycin from thepolymer matrix.

Forming a Primer Layer

The presence of an active ingredient in a polymeric matrix can interferewith the ability of the matrix to adhere effectively to the surface ofthe device. Increasing the quantity of the active ingredient reduces theeffectiveness of the adhesion. High drug loadings in the coating canhinder the retention of the coating on the surface of the device. Aprimer layer can serve as a functionally useful intermediary layerbetween the surface of the device and an active ingredient-containing orreservoir coating. The primer layer provides an adhesive tie between thereservoir coating and the device—which, in effect, would also allow forthe quantity of the active ingredient in the reservoir coating to beincreased without compromising the ability of the reservoir coating tobe effectively contained on the device during delivery and, ifapplicable, expansion of the device.

The composition for a primer layer is prepared by conventional methodswherein all components are combined, then blended. More particularly, apredetermined amount of a polymer or a prepolymer can be added to apredetermined amount of a solvent or a combination of solvents. Themixture can be prepared at ambient pressure and under anhydrousatmosphere. Heating and stirring and/or mixing can be employed to effectdissolution of the polymer into the solvent.

Representative examples of suitable polymers for the primer layerinclude, but are not limited to, polyisocyanates, such astriisocyanurate and polyisocyanate polyether polyurethanes based ondiphenylmethane diisocyanate; acrylates, such as copolymers of ethylacrylate and methacrylic acid; titanates, such as tetra-isopropyltitanate and tetra-n-butyl titanate; zirconates, such as n-propylzirconate and n-butyl zirconate; silane coupling agents, such as3-aminopropyltriethoxysilane and (3-glydidoxypropyl)methyldiethoxysilane; high amine content polymers, such aspolyethyleneamine, polyallylamine, and polylysine; polymers with a highcontent of hydrogen bonding groups, such as polyethylene-co-polyvinylalcohol, ethylene vinyl acetate, and melamine formaldehydes; andunsaturated polymers and prepolymers, such as polycaprolactonediacrylates, polyacrylates with at least two acrylate groups, andpolyacrylated polyurethanes. With the use of unsaturated prepolymers, afree radical or UV initiator can be added to the composition for thethermal or UV curing or cross-linking process, as is understood by oneof ordinary skill in the art.

Representative examples of polymers that can be used for the primermaterial also include those polymers that can be used for the reservoirlayer as described above. The use of the same polymer significantlyreduces or eliminates any interfacial incompatibilities, such as lack ofan adhesive tie or bond, which may exist with the employment of twodifferent polymeric layers.

Ethylene vinyl alcohol is a very suitable choice of polymer for theprimer layer. The copolymer possesses good adhesive qualities to thesurface of a stent, particularly stainless steel surfaces, and hasillustrated the ability to expand with a stent without any significantdetachment of the copolymer from the surface of the stent. The copolymercan comprise a mole percent of ethylene of from about 27% to about 48%.

By way of example, and not limitation, the polymer can comprise fromabout 0.1% to about 35%, more narrowly from about 1% to about 20% byweight of the total weight of the composition, and the solvent cancomprise from about 65% to about 99.9%, more narrowly from about 80% toabout 98% by weight of the total weight of the primer composition. Aspecific weight ratio is dependent on factors such as the material fromwhich the implantable device is made, the geometrical structure of thedevice, the choice of polymer-solvent combination, and the method ofapplication.

In accordance with another embodiment, a fluid can be added to thecomposition to enhance the wetting of the primer composition for a moreuniform coating application. To enhance the wetting of the composition,a suitable fluid typically has a high capillary permeation. Capillarypermeation or wetting is the movement of a fluid on a solid substratedriven by interfacial energetics. Capillary permeation is quantitated bya contact angle, defined as an angle at the tangent of a droplet in afluid phase that has taken an equilibrium shape on a solid surface. Alow contact angle indicates a higher wetting liquid. A suitably highcapillary permeation corresponds to a contact angle less than about 90°.The wetting fluid, typically, should have a viscosity not greater thanabout 50 centipoise, narrowly about 0.3 to about 5 centipoise, morenarrowly about 0.4 to about 2.5 centipoise. The wetting fluid,accordingly, when added to the composition, reduces the viscosity ofcomposition.

The wetting fluid should be compatible with the polymer and the solventand should not precipitate the polymer. The wetting fluid can also actas the solvent. Useful examples of the wetting fluid include, but arenot limited to, tetrahydrofuran (THF), dimethylformamide (DMF),1-butanol, n-butyl acetate, dimethyl acetamide (DMAC), and mixtures andcombinations thereof.

Forming a Finishing Layer

Depending on the polymer used for the reservoir or barrier layers, itmay be advantageous to form a finishing layer that is especiallybiocompatible on the surface of the coating that is exposed to thebiological lumen when inserted into a patient. Representative examplesof suitable biocompatible polymers or biocompatible agents for thefinishing layer include, but are not limited to ethylene vinyl alcoholcopolymer, polyethylene oxide, polyethylene glycol, hyaluronic acid,polyvinyl pyrrolidone, heparin, heparin derivatives such as those havinghydrophobic counterions, and phosphylcholine.

Methods for Applying the Compositions to the Device

Application of the composition can be by any conventional method, suchas by spraying the composition onto the prosthesis or by immersing theprosthesis in the composition. Operations such as wiping,centrifugation, blowing, or other web-clearing acts can also beperformed to achieve a more uniform coating. Briefly, wiping refers tophysical removal of excess coating from the surface of the stent;centrifugation refers to rapid rotation of the stent about an axis ofrotation; and blowing refers to application of air at a selectedpressure to the deposited coating. Any excess coating can also bevacuumed off the surface of the device. The addition of a wetting fluidleads to a consistent application of the composition which also causesthe coating to be uniformly deposited on the surface of the prosthesis.

With the use of the thermoplastic polymers for the primer, such asethylene vinyl alcohol copolymer, polycaprolactone,poly(lactide-co-glycolide), poly(hydroxybutyrate), etc., the depositedprimer composition should be exposed to a heat treatment at atemperature range greater than about the glass transition temperature(T_(g)) and less than about the melting temperature (T_(m)) of theselected polymer. Unexpected results have been discovered with treatmentof the composition under this temperature range, specifically strongadhesion or bonding of the coating to the metallic surface of a stent.The device should be exposed to the heat treatment for any suitableduration of time that would allow for the formation of the primercoating on the surface of the device as well as for the evaporation ofthe solvent or combination of solvent and wetting fluid. It isunderstood that essentially all of the solvent and the wetting fluidwill be removed from the composition, but traces or residues may remainblended with the polymer.

Table 1 lists the T_(g) and T_(m) for some of the polymers used in theembodiments of the present invention. T_(g) and T_(m) of polymers areattainable by one of ordinary skill in the art. The cited exemplarytemperature and time for exposure are provided by way of illustrationand are not meant to be limiting.

TABLE 1 Exemplary Exemplary Duration of T_(g) T_(m) Temperature Time ForPolymer (° C.) (° C.) (° C.) Heating EVAL 55 165 140 4 hourspolycaprolactone −60 60 50 2 hours ethylene vinyl 36 63 45 2 hoursacetate (e.g., 33% vinyl acetate content) Polyvinyl 75-85* 200-220* 1652 hours alcohol *Exact temperature depends on the degree of hydrolysiswhich is also known as the amount of residual acetate.

With the use of one of the aforementioned thermoset primer polymers, theuse of initiators may be required. By way of example, epoxy systemsconsisting of diglycidyl ether of bisphenol A resins can be cured withamine curatives, thermoset polyurethane prepolymers can cured withpolyols, polyamines, or water (moisture), and acrylated urethane can becured with UV light. If baked, the temperature can be above the T_(g) ofthe selected polymer.

With the use of the inorganic primer polymers, such as silanes,titanates, and zirconates, the solvent is allowed to evaporate.

The composition containing the active ingredient can be applied to adesignated region of the primer coating or the surface of the device.The solvent(s) or the combination of solvent(s) and the wetting fluid isremoved from the composition by allowing the solvent(s) or combinationof the solvent(s) and the wetting fluid to evaporate. The evaporationcan be induced by heating the device at a predetermined temperature fora predetermined period of time. For example, the device can be heated ata temperature of about 60° C. for about 12 hours to about 24 hours. Theheating can be conducted in an anhydrous atmosphere and at ambientpressure and should not exceed the temperature which would adverselyaffect the active ingredient. The heating can also be conducted under avacuum condition. It is understood that essentially all of the solventand the wetting fluid will be removed from the composition, but tracesor residues may remain blended with the polymer.

The diffusion barrier layer can be formed on a designated region of theactive ingredient-containing coating subsequent to the evaporation ofthe solvent(s) or solvent(s)/wetting fluid and the drying of the polymerfor the active ingredient-containing coating. Alternatively, inembodiments in which a polymeric reservoir coating is not employed, therate-reducing membrane may be formed directly over active-ingredientcontaining cavities within the surface of the prosthesis. The diffusionbarrier layer can be applied by spraying the composition onto the deviceor immersing the device in the composition, then drying the polymer. Theabove-described processes can be similarly repeated tor the formation ofthe diffusion barrier layer.

Thermal Treatment of the Coating

After the coating has been formed on the implantable device, dependingon the polymers used in the coating, the 40-O-(2-hydroxy)ethyl-rapamycincan diffuse from the polymer matrix at a rate that could be too high forcertain clinical conditions. Accordingly, the coating can be exposed toa temperature that is effective to decrease the diffusion rate of the40-O-(2-hydroxy)ethyl-rapamycin from the polymer matrix. In particular,the coating can be exposed to a sufficient temperature effective todecrease the release rate of the 40-O-(2-hydroxy)ethyl-rapamycin, oranalog or derivative thereof, by about 50% as compared to a controlgroup, as demonstrated in Example 17 below.

Typically, the temperature will be between the glass transitiontemperature (T_(g)) and the melting temperature (T_(m)) of the polymer.For example, the temperature can be the annealing temperature of thepolymer (about equal to T_(g)+T_(m)/2). The thermal treatment can beconducted in an anhydrous atmosphere and at ambient pressure. Thetreatment can also be conducted under a vacuum condition.

The exposure temperature should not adversely affect the characteristicsof the 40-O-(2-hydroxy)ethyl-rapamycin or other active agents present inthe coating. In order to prevent possible degradation of the activeagents or the polymers in the coating, additives can be mixed with thepolymer before or during the coating process to shift the thermalprofile of the polymer (i.e., decrease the T_(g) and T_(m) of thepolymer). For example, a plasticizer, which is usually a low molecularweight nonvolatile molecule, can be dissolved with the polymer beforethe application process. The plasticizer can be an active agent. Arepresentative example of an additive is dioctyl phthalate.

In one embodiment, one of the polymers in the coating exposed to thetemperature is a semi-crystalline (e.g., polyvinyl chloride and EVAL)polymer. Without being bound by any particular theory, it is believedthat the diffusion rate of the active agent from the polymer isdecreased because the thermal radiation increases the percentcrystallinity of the polymer. Others types of energy, such as RF energy,can also be used to increase the percent crystallinity. “Percentcrystallinity” refers to the percentage of the polymer material that isin a crystalline form. Those of ordinary skill in the art understandthat there are several methods for determining the percent crystallinityin polymers. These methods are, for example, described in L. H.Sperline, Introduction to Physical Polymer Science (3rd ed. 2001). Thefirst involves the determination of the heat of fusion of the wholesample by calorimetric methods. The heat of fusion per mole ofcrystalline material can be estimated independently by melting pointdepression experiments.

A second method involves the determination of the density of thecrystalline portion via X-ray analysis of the crystal structure, anddetermining the theoretical density of a 100% crystalline material. Thedensity of the amorphous material can be determined from anextrapolation of the density from the melt to the temperature ofinterest. Then the percent crystallinity is given by:

${\% \mspace{14mu} {Crystallinity}} = {\frac{\rho_{exptl} - \rho_{amorph}}{\rho_{100\%_{cryst}} - \rho_{amorph}} \times 100}$

where ρ_(exptl) represents the experimental density, and ρ_(amorph) andρ_(100% cryst) are the densities of the amorphous and crystallineportions, respectively.

A third method stems from the fact that X-ray diffraction depends on thenumber of electrons involved and is thus proportional to the density.Besides Bragg diffraction lines for the crystalline portion, there is anamorphous halo caused by the amorphous portion of the polymer. Theamorphous halo occurs at a slightly smaller angle than the correspondingcrystalline peak, because the atomic spacings are larger. The amorphoushalo is broader than the corresponding crystalline peak, because of themolecular disorder. This third method can be quantified by thecrystallinity index, CI, where

${CI} = \frac{A_{c}}{A_{a} + A_{c}}$

and where A_(c) and A_(a) represent the area under the Bragg diffractionline and corresponding amorphous halo, respectively.

The heat emitter used to thermal treat the coating can be any apparatusthat emits thermal radiation. For example, the heat emitter can be acauterizer tip. The heat emitter can also be a blower that includes aheating device so that the blower can direct a warm gas (e.g., air,argon or nitrogen) onto the implantable device. The heating device canbe any heating device as known by those of ordinary skill in the art.For example, the heating device can be an electric heater incorporatingheating coils.

In one embodiment of the present invention, the thermal radiation fromthe heat emitter can be directed to only certain portions of theimplantable device or only for certain durations so that the diffusionrates of the 40-O-(2-hydroxy)ethyl-rapamycin from the polymer differs invarious portions of the coating. In one example, the implantable devicecan have two or more segments along the longitudinal axis of theimplantable device, such as a first segment, a second segment and athird segment. The thermal radiation could be directed substantiallyonly at the first segment and the third segment, for instance, by usinga cauterizer tip. Alternatively, the thermal radiation could be sethigher for the first and third segments, or the thermal radiation couldbe directed at the first and third segments for a longer duration thanthe second segment. As a result, the polymer along the first segment andthe third segment would have a greater percent crystallinity than thepolymer along the second segment. Therefore, the diffusion rates of theactive agent from the polymer matrix along the first segment and thethird segment would be less than the diffusion rate along the secondsegment.

In another embodiment, by limiting the time that the coating is exposedto thermal radiation so that the percent crystallinity is not maximizedthroughout the entire thickness of the coating, the shallower regions ofthe coating will have a higher percent crystallinity than the deeperregions. In a particular example, if the coating has four regions withthe fourth region as the deepest, by limiting the thermal treatment, thefirst or shallowest region would have a higher percent crystallinitythan the fourth or deepest region. One of ordinary skill in the art willunderstand that the duration and temperature of the exposure will dependon the desired diffusion rate of the polymer, and the inherentcharacteristics of the polymers used in the coating.

Sterilization of the Implantable Device

After the implantable device has been coated according to the variousembodiments of the present invention, the implantable device can besterilized by various methods. According to conventional thought, acoating containing 40-O-(2-hydroxy)ethyl-rapamycin cannot be sterilizedwith many techniques because the 40-O-(2-hydroxy)ethyl-rapamycin isdegraded by the processes. For example, it was thought that a polymercoating containing 40-O-(2-hydroxy)ethyl-rapamycin could not besterilized with an e-beam procedure because the free radicals producedduring the process would degrade the 40-O-(2-hydroxy)ethyl-rapamycin.Similarly, it has been thought that exposing a coating with40-O-(2-hydroxy)ethyl-rapamycin to ethylene oxide or peroxide gas wouldalso degrade the 40-O-(2-hydroxy)ethyl-rapamycin. However, it hasunexpectedly been found that the coatings of the present inventionprotect the 40-O-(2-hydroxy)ethyl-rapamycin during sterilizationprocedures (e.g., using an e-beam or ethylene oxide process). In fact,subsequent to sterilization, the peak purity of the40-O-(2-hydroxy)ethyl-rapamycin has been greater than 90% when includedin the coatings of the present invention.

In an embodiment of the present invention, the particular procedure usedto sterilize the coating can also be used to expose the coating to atemperature that is effective to decrease the diffusion rate of the40-O-(2-hydroxy)ethyl-rapamycin from the polymer matrix. In particular,during the sterilization procedure (e.g., the ethylene oxide procedure)the coating can be exposed to a sufficient temperature effective todecrease the release rate of the 40-O-(2-hydroxy)ethyl-rapamycin, oranalog or derivative thereof, by about 50% as compared to a controlgroup.

Examples of the Device

The device or prosthesis coated in accordance with embodiments of thepresent invention may be any suitable medical substrate that can beimplanted in a human or veterinary patient. Examples of such implantabledevices include self-expandable stents, balloon-expandable stents,stent-grafts, grafts (e.g., aortic grafts), artificial heart valves,cerebrospinal fluid shunts, pacemaker electrodes, and endocardial leads(e.g., FINELINE and ENDOTAK, available from Guidant Corporation, SantaClara, Calif.). The underlying structure of the device can be ofvirtually any design. The device can be made of a metallic material oran alloy such as, but not limited to, cobalt chromium alloy (ELGILOY),stainless steel (316L), high nitrogen stainless steel, e.g., BIODUR 108,cobalt chrome alloy L-605, “MP35N,” “MP20N,” ELASTINITE (Nitinol),tantalum, nickel-titanium alloy, platinum-iridium alloy, gold,magnesium, or combinations thereof. “MP35N” and “MP20N” are trade namesfor alloys of cobalt, nickel, chromium and molybdenum available fromStandard Press Steel Co., Jenkintown, Pa. “MP35N” consists of 35%cobalt, 35% nickel, 20% chromium, and 10% molybdenum. “MP20N” consistsof 50% cobalt, 20% nickel, 20% chromium, and 10% molybdenum. Devicesmade from bioabsorbable or biostable polymers could also be used withthe embodiments of the present invention.

The embodiments of the present invention may be particularly useful forthe coatings of small vessel stents. Small vessels stents can begenerally categorized as having inner diameters of less than 2.5 mm inan expanded state. Because of their small size, small vessel stentsoffer unique challenges for drug delivery. In particular, as compared toconventionally sized stents, small vessel stents have a greatersurface:volume ratio. Therefore, when a small vessel stent is insertedinto a biological lumen, the vessel tissue surrounding a small vesselstent is exposed to a greater concentration of polymer and active agent.

The various embodiments of the present invention can be used to addresssome of the challenges offered by the use of small vessel stents. Forexample, it is thought that it is especially important that small vesselstents have lower amounts of polymer in their coatings, as compared tolarger sized stents, in order to reduce the risk of an inflammatoryresponse by the vessel tissue. However, it may also be important to havea barrier layer on the stent coating in order to have a low release rateof the active agents, such as 40-O-(2-hydroxy)ethyl-rapamycin. With theinclusion of the barrier layer, the amount of polymer on the coating maybe sufficient to cause an unwanted inflammatory response. In order toaddress these countervailing concerns, one approach would be to providea thinner barrier layer on the polymer matrix as compared to largersized stents, and then heat treat the barrier layer to increase thecrystallinity of the barrier layer polymer, thereby decreasing therelease rate of the active agent from the reservoir region. In analternative embodiment, the polymer used for the barrier layer caninitially have a very high percent crystallinity. In yet anotherembodiment, the reservoir layer can be heat treated to reduce therelease rate of active agent from the reservoir region without the useof a barrier layer.

In another particular example, it is thought that it is especiallyimportant for small vessel stems to have a biocompatible coating. Oneapproach to address this need is to provide a finishing layer on thestent that contains a highly biocompatible polymer such as polyethyleneglycol, or biocompatible agents such as heparin. For example, afinishing layer can be applied over a barrier layer so that the coatingoffers a usefully low release rate of an active agent and also providesa highly biocompatible coating.

Coating

Some of the various embodiments of the present invention are illustratedby FIGS. 1A, 1B, and 1C. The Figures have not been drawn to scale, andthe thickness of the various layers have been over or under emphasizedfor illustrative purposes.

Referring to FIG. 1A, a body of a medical substrate 20, such as a stent,is illustrated having a surface 22. Medical substrate 20 includescavities or micropores 24 formed in the body for releasably containingan active ingredient, as illustrated by dotted region 26. A barrierlayer or rate-reducing membrane 28 is disposed on surface 22 of medicalsubstrate 20, covering cavities 24. Barrier layer 28 functions to reducethe rate of release of an active agent (e.g.,40-O-(2-hydroxy)ethyl-rapamycin) from medical substrate 20.

Referring to FIG. 1B, medical substrate 20 is illustrated having aprimer layer 30 formed on surface 22. An active agent-containing orreservoir coating 32 is deposited on primer layer 30. Primer layer 30serves as an intermediary layer for increasing the adhesion betweenreservoir coating 32 and surface 22. Increasing the amount of activeingredient admixed within the polymer diminishes the adhesiveness ofreservoir layer 32 to surface 22. Accordingly, using an activeagent-free polymer as an intermediary primer layer 30 allows for ahigher active ingredient content for reservoir layer 32. Barrier layer28 is formed over at least a selected portion of reservoir layer 32. Oneof ordinary skill in the art can appreciate that barrier layer 28 can bedeposited only on selected areas of reservoir layer 32 so as to providea variety of selected release parameters. Such selected patterns maybecome particularly useful if a combination of active agents are used,each of which requires a different release parameter.

FIG. 1C illustrates medical substrate 20 having a first reservoir layer32A disposed on a selected portion of surface 22 of medical substrate20. First reservoir layer 32A contains a first active agent, e.g.,40-O-(2-hydroxy)ethyl-rapamycin. A second reservoir layer 32B can alsobe disposed on surface 22. Second reservoir layer 32B contains a secondactive ingredient, e.g., taxol. First and second reservoir layers 32Aand 32B are covered by first and second barrier layers 28A and 28B,respectively. In accordance with one embodiment, the polymeric materialin barrier layer 28B has been exposed to thermal treatment, whereas thepolymeric material in barrier layer 28A has not. As a result, thepolymeric material in barrier 28B has a higher percent crystallinitytitan the polymeric material in barrier layer 28A. Accordingly, byproducing a coating such as the one shown in FIG. 1C, a wide array ofrelease parameters can be obtained for any selected combination ofactive agents.

Barrier layer 28 can have any suitable thickness, as the thickness ofbarrier layer 28 is dependent on parameters such as, but not limited to,the desired rate of release and the procedure for which the stent willbe used. For example, barrier layer 28 can have a thickness of about 0.1to about 10 microns, more narrowly from about 0.25 to about 5 microns.

By way of example, and not limitation, the impregnated reservoir layer32 can have a thickness of about 0.5 microns to about 1.5 microns. Theparticular thickness of reservoir layer 32 is based on the type ofprocedure for which medical substrate 20 is employed and the amount ofthe active agent to be delivered. The amount of the active agent to beincluded on the prosthesis can be further increased by applying aplurality of reservoir layers 32 on top of one another. The optionalprimer layer 30 can have any suitable thickness, examples of which canbe in range of about 0.1 to about 10 microns, more narrowly about 0.1 toabout 2 microns.

Method of Use

In accordance with the above-described method, the active agent can beapplied to a device, e.g., a stent, retained on the device duringdelivery and released at a desired control rate and for a predeterminedduration of time at the site of implantation. A stent having theabove-described coating layers is useful for a variety of medicalprocedures, including, by way of example, treatment of obstructionscaused by tumors in bile ducts, esophagus, trachea/bronchi and otherbiological passageways. A stent having the above-described coatinglayers is particularly useful for treating occluded regions of bloodvessels caused by abnormal or inappropriate migration and proliferationof smooth muscle cells, thrombosis, and restenosis. Stents may be placedin a wide array of blood vessels, both arteries and veins.Representative examples of sites include the iliac, renal, and coronaryarteries.

Briefly, an angiogram is first performed to determine the appropriatepositioning for stent therapy. Angiography is typically accomplished byinjecting a radiopaque contrasting agent through a catheter insertedinto an artery or vein as an x-ray is taken. A guidewire is thenadvanced through the lesion or proposed site of treatment. Over theguidewire is passed a delivery catheter, which allows a stent in itscollapsed configuration to be inserted into the passageway. The deliverycatheter is inserted either percutaneously, or by surgery, into thefemoral artery, brachial artery, femoral vein, or brachial vein, andadvanced into the appropriate blood vessel by steering the catheterthrough the vascular system under fluoroscopic guidance. A stent havingthe above-described coating layers may then be expanded at the desiredarea of treatment. A post insertion angiogram may also be utilized toconfirm appropriate positioning.

EXAMPLES

The embodiments of the present invention will be illustrated by thefollowing set forth examples.

Example 1

35 13 mm PENTA stents (available from Guidant Corporation) were coatedby spraying a 2% (w/w) solution of poly(ethylene-co-vinyl alcohol) (44mole % ethylene) (“EVAL”) in 98% (w/w) dimethylacetamide. The solventwas removed by baking at 140° C. for 2 hours. A solution of 1.9% (w/w)EVAL and 0.7% (w/w) 40-O-(2-hydroxy)ethyl-rapamycin in a mixture of68.2% (w/w) dimethylacetamide and 29.2% (w/w) ethanol was spray coatedonto the stents to a thickness with a target of 175 μg of40-O-(2-hydroxy)ethyl-rapamycin on each stent. The stents were thenbaked at 50° C. for 2 hours. A barrier layer was formed by spraying thestents with a 4% (w/w) solution of EVAL in a mixture of 76% (w/w)dimethylacetamide and 20% (w/w) pentane. Another 2 hour bake at 50° C.was performed to remove the solvent.

A select number of stents were analyzed to compare the target coatingformulation with the final coating formulation. The results are asfollows: For the primer layer, there was a target dry weight of 40 μg ofpolymer, and a measured average dry weight of 43±3 μg of polymer. Forthe reservoir layer, the target drug:polymer ratio was 1:2.857, thetarget dry weight for the entire reservoir coating was 675 μg and theaverage actual dry weight was 683±19 μg. Also for the reservoir layer,the average total drug content of the stent coatings was determined bythe process described in Example 2. The average drug content was 133 μgor 152 μg/cm². For the barrier layer, the target dry weight of polymerwas 300 μg and the measured average dry weight was 320±13 μg.

Example 2

A drug-coated stent was placed in a volumetric flask. An appropriateamount of the extraction solvent acetonitrile with 0.02% BHT asprotectant was added (e.g., in a 10 ml volumetric flask, with about 9 mlsolvent added). The flask was sonicated for a sufficient time to extractall of the drug from the reservoir region. Then, the solution in theflask was filled to mark with the solvent solution. The drug solutionwas the analyzed by HPLC. The HPLC system consisted of a Waters 2690system with an analytical pump, a column compartment (set at 40° C.), anauto-sampler, and a 996 PDA detector. The column was an YMC Pro C18 (150mm×4.6 I.D., 3 μm particle size), maintained at a temperature of 40° C.The mobile phase consisted of 75% acetonitrile and 25% 20 mMolarammonium acetate. The flow rate was set on 1 ml/min. The HPLC releaserate results were quantified by comparing the results with a referencestandard. The total drug content of the stent was then calculated.

Example 3

34 13 mm PENTA stents were coated by spraying a 2% (w/w) solution ofEVAL and 98% (w/w) dimethylacetamide. The solvent was removed by bakingat 140° C. for 2 hours. A solution of 1.9% (w/w) EVAL and 1.1% (w/w)40-O-(2-hydroxy)ethyl-rapamycin in a mixture of 67.9% (w/w)dimethylacetamide and 29.1% (w/w) ethanol was spray coated onto thestents to a thickness with a target of 275 μg of40-O-(2-hydroxy)ethyl-rapamycin on each stent. The stents were thenbaked at 50° C. for 2 hours. A barrier layer was formed by spraying thestents with a 4% (w/w) solution of EVAL in a mixture of 76 % (w/w)dimethylacetamide and 20% (w/w) pentane. Another 2 hour bake at 50° C.was performed to remove the solvent.

A select number of stents were analyzed to compare the target coatingformulation with the final coating formulation. The results are asfollows: For the primer layer, there was a target dry weight of 40 μg ofpolymer, and a measured average dry weight of 43±3 μg of polymer. Forthe reservoir layer, the target drug:polymer ratio was 1:1.75, thetarget dry weight for the entire reservoir coating was 757 μg and theaverage actual dry weight was 752±23 μg. Also for the reservoir layer,the average total drug content of the stent coatings was determined bythe process described in Example 2. The average drug content was 205 μgor 235 μg/cm². For the barrier layer, the target dry weight of polymerwas 200 μg and the measured average dry weight was 186±13 μg.

Example 4

24 13 mm PENTA stents were coated by spraying a 2% (w/w) solution ofEVAL and 98% (w/w) dimethylacetamide. The solvent was removed by bakingat 140° C. for 2 hours. A solution of 1.9% (w/w) EVAL and 1.2% (w/w)40-O-(2-hydroxy)ethyl-rapamycin in a mixture of 67.8% (w/w)dimethylacetamide and 29.1% (w/w) ethanol was spray coated onto thestents to a thickness with a target of 325 μg of40-O-(2-hydroxy)ethyl-rapamycin on each stent. The stents were thenbaked at 50° C. for 2 hours. A barrier layer was formed by spraying thestents with a 4% (w/w) solution of EVAL in a mixture of 76 % (w/w)dimethylacetamide and 20% (w/w) pentane. Another 2 hour bake at 50° C.was performed to remove the solvent.

A select number of stents were analyzed to compare the target coatingformulation with the final coating formulation. The results are asfollows: For the primer layer, there was a target dry weight of 40 μg ofpolymer, and a measured average dry weight of 41±2 μg of polymer. Forthe reservoir layer, the target drug:polymer ratio was 1:1.6, the targetdry weight for the entire reservoir coating was 845 μg and the averageactual dry weight was 861±16 μg. Also for the reservoir layer, theaverage total drug content of the stent coatings was determined by theprocess described in Example 2. The average drug content was 282 μg or323 μg/cm². For the barrier layer, the target dry weight of polymer was125 μg and the measured average dry weight was 131±9 μg.

Example 5

This Example 5 is referred to as the “Release Rate Profile Procedure.” Adrug-coated stent was placed on a stent holder of a Vankel Bio-Disrelease rate tester (Vankel, Inc., Cary, N.C.). The stent was dippedinto an artificial medium which stabilizes the40-O-(2-hydroxy)ethyl-rapamycin in the testing solution, including aphosphate buffer saline solution (10 mM, pH 7.4) with 1% TRITON X-100(Sigma Corporation), for a designated amount of time (e.g., 3 hours).Then the solution was analyzed for the amount of drug released from thestent coating using an HPLC process. The HPLC system consisted of aWaters 2690 system with an analytical pump, a column compartment (set at40° C., an auto-sampler, and a 996 PDA detector. The column was an YMCPro C18 (150 mm×4.6 I.D., 3 μm particle size), maintained at atemperature of 40° C. The mobile phase consisted of 75% acetonitrile and25% 20 mMolar ammonium acetate. The flow rate was set on 1 ml/min. Afterthe drug solution was analyzed by HPLC the results were quantified bycomparing the release rate results with a reference standard.

If the experimental protocol required that the stent coating besubjected to experimental conditions for an additional time, the stentwas then dipped in a fresh medium solution for the necessary amount oftime (e.g., another 3 hours) and the drug released in the solution wasanalyzed again according to the HPLC procedure described above. Theprocedure was repeated according to the number of data points required.The release rate profile could then be generated by plotting cumulativedrug released in the medium vs. time.

Example 6

The release rate of 40-O-(2-hydroxy)ethyl-rapamycin from the stents withcoatings produced by the processes under Examples 1, 3 and 4 were testedusing the in vitro HPLC process as described in Example 5. The solutionfor each stent underwent two HPLC runs, and the results were averaged.

The following Table 2 summarizes the results of the release rateprocedure for two stents from Example 1:

TABLE 2 Time (hrs) 3 6 9 12 23 32 48 Cumulative 3.72 5.62 7.12 8.4312.28 15.31 20.28 Release from Stent 1 (μg) Cumulative 4.18 6.53 8.5410.29 15.64 19.66 26.3 Release from Stent 2 (μg)

The following Table 3 summarizes the results of the release rateprocedure for two stents from Example 3:

TABLE 3 Time (hrs) 3 6 9 12 23 32 48 Cumulative 29.73 45.35 57.79 68.1995.2 110.85 130.75 Release from Stent 1 (μg) Cumulative 26.36 41.2 53.563.99 93.93 112.31 135.7 Release from Stent 2 (μg)

The following Table 4 summarizes the results of the release rateprocedure for two stents from Example 4:

TABLE 4 Time (hrs) 3 6 9 12 23 32 48 Cumulative 46.24 67.4 82.79 94.92124.72 141.96 165.12 Release from Stent 1 (μg) Cumulative 44.66 66.7482.26 94.49 123.92 140.07 159.65 Release from Stent 2 (μg)

A comparison of the release rates for tits stents from Examples 1, 3 and4 is graphically shown in FIG. 2.

Example 7

The following Example 7 is referred to as the “3 day In Vivo ReleaseRate Procedure” or the “9 day In Vivo Release Rate Procedure,” dependingon the number of days the stents are inserted into the experimentalanimal. The following are the materials used for this Example:

-   -   1. Experimental animal: One 30-45 kg Yorkshire cross pig;    -   2. BMW™ wires 0.014″, 190 cm;    -   3. Guide wire 0.035″, 190 cm;    -   4. Viking guide catheters, 7F;    -   5. Introducer sheaths (8-10F);    -   6. ACS 20/20 Indeflator™ Inflation Device;    -   7. Saline; solution with heparin;    -   8. Nitroglycerin, Lidocaine, other inotropic/chronotropic drugs;    -   9. Standard surgical equipment, anesthetic, and medications as        necessary;    -   10. Respiratory and hemodynamic monitoring systems;    -   11. Positive pressure ventilator and associated breathing        circuits;    -   12. ACT machine and accessories;    -   13. PTCA accessories;    -   14. Ambulatory defibrillator,    -   15. Fluoroscopy equipment; and    -   16. Non-ionic contrast agent;

The following was the procedure used for this Example:

A. Animal Preparation.

-   -   1. Administer Aspirin (325 mg PO) once daily starting one day        prior to stent implantation.    -   2. Sedate the pig.    -   3. Intubate the trachea via an oral approach.    -   4. Deliver isoflurane (up to about 5%) to achieve and maintain        an adequate plane of anesthesia.    -   5. Shave the sheath introduction area free of hair and scrub the        surgical site with surgical soap and/or antiseptic solution.    -   6. Place a 7F introducer sheath into the right or left femoral        artery.    -   7. Obtain an arterial blood sample for a baseline ACT.    -   8. Administer heparin 200 units/kg IV (not to exceed 100,000        units) and obtain a blood sample for measurement of ACT 5-10        minutes later.    -   9. Repeat heparin as needed to maintain ACT≧300 seconds.    -   10. Measure and record arterial blood pressure, heart rate and        electrocardiogram (ECG).

B. Angiography for Vessel Selection.

-   -   1. Advance the guiding catheter over the guidewire into the        aortic arch and cannulate the desired vessel.    -   2. Administer nitroglycerin (200 μg) intra-luminally prior to        baseline angiography.    -   3. Perform baseline angiogram and record images on cine.    -   4. With the diameter of the guiding catheter as a reference,        select vasculature that will allow a target stent to artery        ratio of about 1.1:1.0.

C. Stent Preparation and Deployment.

-   -   1. Perform online QCA and measure baseline proximal, target, and        distal reference sites.    -   2. Administer nitroglycerin (200 μg) intra-luminally prior to        stent deployment, then as needed to control coronary artery        vasospasm.    -   3. Inspect the stent delivery system. Ensure that the stent is        correctly positioned on the balloon. Inspect the stent for any        abnormalities.    -   4. Flush guidewire lumen with heparinized saline until fluid        exits the guidewire notch.    -   5. Prepare Indeflator/syringe with diluted (approximately 50:50)        contrast medium.    -   6. Attach syringe to test catheter inflation port; use standard        techniques to fill the inflation lumen with diluted contrast.    -   7. Purge syringe and test catheter inflation lumen of all air.    -   8. Purge Indeflator of all air and attach to test catheter        inflation port.    -   9. Position an appropriate guidewire in the distal bed of the        target artery.    -   10. Insert the stent delivery system through the guiding        catheter over the guidewire.    -   11. Advance the stent delivery system to the pre-selected        arterial deployment site.    -   12. Position balloon for inflation.    -   13. Refer to IFU for inflation strategy. If no IFU available,        inflate the balloon at a slow steady rate to a pressure that        expands the stent to the desired diameter. Hold at this pressure        for 30 seconds.    -   14. Record inflated balloon by pulling image on cine. Perform        on-line QCA and measure the inflated balloon diameter.    -   15. Deflate balloon by pulling negative pressure. While        withdrawing the system, observe tactually and fluoroscopically.        Record any resistance.    -   16. Administer nitroglycerin (200 μg) intra-luminally.    -   17. Assess patency, deployment and placement of stent via        coronary angiography.    -   18. Assess TIMI angiographic low grade.    -   19. Record on cine and video.    -   20. Measure post-proximal, target, and distal MLD with QCA.    -   21. Repeat Section C with remaining stent delivery system.    -   22. Measure and record heart rate, arterial blood pressure and        electrocardiogram (ECG).

D. Stent Procedure End.

-   -   1. Remove the guidewire, guiding catheter and introducer sheath.    -   2. Remove introducer sheath from the femoral artery.    -   3. Apply pressure to the femoral artery at the side of sheath        entry.    -   4. Allow the animal to recover from anesthesia in an individual        cage.    -   5. Give Buprenorphine (0.05 mg/kg) PRN as needed for pain.    -   6. Administer Ticiopidine (250 mg PO) and aspirin (325 mg PO)        once daily until date of follow-up angiography.

E. Study End.

-   -   1. Euthanize the pig with an overdose of barbiturates and/or        potassium chloride.    -   2. Excise the heart without flushing the vessels.    -   3. Harvest all stented arteries.    -   4. Remove the stent from all treated arteries and place them in        dark colored amber vials for subsequent drug concentration        analysis.    -   5. Snap freeze the arterial tissue in liquid nitrogen and store        at −70° C. until subsequent analysis of tissue for drug        concentrations as determined by HPLC.

The stents harvested from the experimental animals were tested using anHPLC procedure to determine how much drug remained on the stents. Adrug-coated stent removed from the experimental animal was placed in avolumetric flask. An appropriate amount of the extraction solventacetonitrile with 0.02% BHT as protectant was added (e.g., in a 10 mlvolumetric flask, with about 9 ml solvent added). The flask wassonicated for a sufficient time to extract all of the drug from thereservoir region. Then, the solution in the flask, was filled to markwith the solvent solution. The HPLC system consisted of a Waters 2690system with an analytical pump, a column compartment (set at 40° C.), anauto-sampler, and a 996 PDA detector. The column was an YMC Pro C18 (150mm×4.6 I.D., 3 μm particle size), maintained at a temperature of 40° C.The mobile phase consisted of 75% acetonitrile and 25% 20 mMolarammonium acetate. The flow rate was set on 1 ml/min. The HPLC releaserate results were quantified by comparing the results with a referencestandard. The total drug released in vivo was the difference between theaverage drug loaded on the stents and the amount of drug remaining onthe stents after the stent implantation into the experimental animal.

Example 8

The release rate of 40-O-(2-hydroxy)ethyl-rapamycin from the stents withcoatings produced by the process under Example 1 were tested using a 3day in vivo process as described in Example 7. In particular, stentsfrom Example 1 were implanted into experimental animals and then thestents were tested by HPLC to determine how much40-O-(2-hydroxy)ethyl-rapamycin diffused from the stent coating into theblood vessel. According to the HPLC analysis, 21.8 μg of the40-O-(2-hydroxy)ethyl-rapamycin was released from the coating in 3 days,or 16.4% of the total drug content of the coating.

Example 9

The release rate of 40-O-(2-hydroxy)ethyl-rapamycin from the stents withcoatings produced by the process under Example 3 were tested using a 3day in vivo process as described in Example 7. In particular, stentsfrom Example 3 were implanted into experimental animals and then thestents were tested by HPLC to determine how much40-O-(2-hydroxy)ethyl-rapamycin diffused from the stent coating into theblood vessel. According to the HPLC analysis, 7.8 μg of the40-O-(2-hydroxy)ethyl-rapamycin was released from the coating in 3 days,or 3.8% of the total drug content of the coating.

Example 10

The release rate of 40-O-(2-hydroxy)ethyl-rapamycin from the stents withcoatings produced by the process under Example 4 were tested using a 3day in vivo process as described in Example 7. In particular, stentsfrom Example 4 were implanted into experimental animals and then thestents were tested by HPLC to determine how much40-O-(2-hydroxy)ethyl-rapamycin diffused from the stent coating into theblood vessel. According to the HPLC analysis, 50.8 μg of the40-O-(2-hydroxy)ethyl-rapamycin was released from the coating in 3 days,or 18% of the total drug content of the coating.

Example 11

The release rate of 40-O-(2-hydroxy)ethyl-rapamycin from the stents withcoatings produced by the process under Example 3 were tested using a 9day in vivo process as described in Example 7. In particular, stentsfrom Example 3 were implanted into experimental animals and then thestents were tested by HPLC to determine how much40-O-(2-hydroxy)ethyl-rapamycin diffused from the stent coating into theblood vessel. According to the HPLC analysis, 29.7%, of the40-O-(2-hydroxy)ethyl-rapamycin was released from the coating in 9 days.

Example 12

The release rate of 40-O-(2-hydroxy)ethyl-rapamycin from the stents withcoatings produced by the process under Example 4 were tested using a 9day in vivo process as described in Example 7. In particular, stentsfrom Example 4 were implanted into experimental animals and then thestents were tested by HPLC to determine how much40-O-(2-hydroxy)ethyl-rapamycin diffused from the stent coating into theblood vessel. According to the HPLC analysis, 39.4% of the40-O-(2-hydroxy)ethyl-rapamycin was released from the coating in 9 days.

Example 13

A 13 mm PIXEL stent (available from Guidant Corporation) was coated. Thestent had a yellowish-gold coating that included ethylene vinyl alcoholcopolymer and actinomycin D. The ends of the stent were heated with acauterizer tip for fifteen (15) seconds at a current setting of 2.2Amps, which corresponded to a temperature of about 106° C. at a distanceof about 0.006 inches from the stent.

After the stent was exposed to heat from the cauterizer tip, the stentwas submerged in a 50% (w/w) methanol:water bath. After twenty-four (24)hours, the stent was observed to have drug present at the stent endrings as indicated by a yellowish hue. The middle section of the stent,however, was clear, indicating that the drug had been released throughthe polymer. This process was repeated on 40 stents yielding similarresults for all the stents.

Example 14

13 mm PIXEL stents were coated. The stents had yellowish-gold coatingsthat included ethylene vinyl alcohol copolymer and actinomycin D. Thestents were separated into three experimental groups, and the ends ofthe stents were heated with a cauterizer tip according to the parametersshown in Table 5 for each group. After the stents were exposed to heatfrom the cauterizer tip, the stent was submerged in a 50% (w/w)methanol:water bath. After twenty-four (24) hours, the stents wereobserved as summarized in Table 5.

TABLE 5 Exposure Experimental Current Time Group (Amps) (Seconds)Observation 1 2.0 10 Least gold coloration in the end sections comparedto the stents from Experimental Groups 2 and 3, indicating the leastamount of drug remaining in the stent coating. 2 2.2 8 Moderate goldcoloration in the end sections. 3 2.4 5 Most gold coloration in the endsections compared to the stents from Experimental Groups 1 and 2indicating the most amount of drug ramaining in the stent coating.

It was observed that the coating in the middle section of the stents,which did not have significant exposure to heat from the cauterizer tip,was clear. This indicates that the drug had been eluted from the stents.On the other hand, the end rings of the stents which had been exposed toheat from the cauterizer tip still appealed gold in color, indicatingthe presence of drug in the stent coating. The results above indicatethat varying the amount of time and heat exposure can modify the elutionrate of drug from the stent.

Example 15

8 mm PIXEL stents were coated by spraying a 2% (w/w) solution of EVALand 98% (w/w) dimethylacetamide. The solvent was removed by baking at140° C. for 2 hours. A solution of EVAL and40-O-(2-hydroxy)ethyl-rapamycin in a mixture of 70% (w/w)dimethylacetamide and 30% (w/w) ethanol was spray coated onto thestents. The stents were then baked at 50° C. for 2 hours. A barrierlayer was formed by spraying the stents with a solution of EVAL in amixture of 80% (w/w) dimethylacetamide and 20% (w/w) pentane. Another 2hour bake at 50° C. was performed to remove the solvent.

A select number of stents were analyzed to compare the target coatingformulation with the final coating formulation. The results are asfollows: For the primer layer, there was a target dry weight of 26 μg ofpolymer, and a measured average dry weight of 28±3 μg of polymer. Forthe reservoir layer, the target drug:polymer ratio was 1:1.25, and themeasured average drug content was 128 μg. For the barrier layer, themeasured average dry weight was 84 μg.

Example 16

8 mm PIXEL stents were coated by spraying a 2% (w/w) solution of EVALand 98% (w/w) dimethylacetamide. The solvent was removed by baking at140° C. for 2 hours. A solution of EVAL and40-O-(2-hydroxy)ethyl-rapamycin in a mixture of 70% (w/w)dimethylacetamide and 30% (w/w) ethanol was spray coated onto thestents. The stents were then baked at 50° C. for 2 hours. A barrierlayer was formed by spraying the stents with a solution of EVAL in amixture of 80% (w/w) dimethylacetamide and 20% (w/w) pentane. Another 2hour bake at 50° C. was performed to remove the solvent.

A select number of stents were analyzed to compare the target coatingformulation with the final coating formulation. The results are asfollows: For the primer layer, there was a target dry weight of 26 μg ofpolymer, and a measured average dry weight of 28±2 μg of polymer. Forthe reservoir layer, the target drug:polymer ratio was 1:1.5, and themeasured average drug content was 130 μg. For the barrier layer, themeasured average dry weight was 81 μg.

After the solvent had been substantially removed and the coatings hadbeen formed, a select number of stents were then heat treated byexposing the stents to a heat of 80° C. for 2 hours.

Example 17

The release rate of 40-O-(2-hydroxy)ethyl-rapamycin from the stents withcoatings produced by the processes under Examples 15 and 16 were testedusing the process described in Example 5. The following Table 6summarizes the results of the release rate procedure for three stentsfrom Example 15:

TABLE 6 Time (hrs) 3 6 9 12 24 32 48 Cumulative 15.44 24.63 32.20 38.4356.04 64.81 77.36 Release from Stent 1 (μg) Cumulative 12.70 21.29 28.5734.55 51.19 59.27 71.15 Release from Stent 2 (μg) Cumulative 13.00 21.9229.31 35.40 52.55 60.48 72.05 Release from Stent 3 (μg)

The following Table 7 summarizes the results of the release rateprocedure for three stents from Example 16:

TABLE 7 Time (hrs) 3 6 9 12 24 32 48 Cumulative 5.52 9.37 12.73 15.7124.33 29.20 38.02 Release from Stent 1 (μg) Cumulative 6.73 10.86 14.3917.41 25.99 30.29 38.00 Release from Stent 2 (μg) Cumulative 5.76 9.1412.02 14.50 21.21 24.61 31.23 Release from Stent 3 (μg)

A comparison of the release rates tor the stents from Examples 15-16 isgraphically shown in FIG. 3. The results unexpectedly show that thestent coatings that were exposed to thermal treatment in Example 16 havea significantly lower release rate than the stent coatings of Example15.

Example 18

This Example 18 is referred to as the “Porcine Serum Release RateProcedure.” A drug-coated stent was placed on a stent holder of a VankelBio-Dis release rate tester. The stent was dipped into porcine serum,with 0.1% sodium azide added, for 24 hrs. The stent was removed from theporcine serum and the drug solution analyzed by an HPLC procedure todetermine how much drug was released into the porcine serum. The HPLCsystem consisted of a Waters 2690 system with an analytical pump, acolumn compartment (set at 40° C.), an auto-sampler, and a 996 PDAdetector. The column was an YMC Pro C18 (150 mm×4.6 I.D., 3 μm particlesize), maintained at a temperature of 40° C. The mobile phase consistedof 75% acetonitrile and 25% 20 mMolar ammonium acetate. The flow ratewas set on 1 ml/min. The HPLC release rate results were quantified bycomparing the results with a reference standard.

Example 19

13 mm PENTA stents were coated by spraying a 2% (w/w) solution of EVALand 98% (w/w) dimethylacetamide. The solvent was removed by baking at140° C. for 2 hours. A solution of EVAL and40-O-(2-hydroxy)ethyl-rapamycin in a mixture of 70% (w/w)dimethylacetamide and 30% (w/w) ethanol was spray coated onto thestents. The stents were then baked at 50° C. for 2 hours. A barrierlayer was formed by spraying the stents with a solution of EVAL in amixture of 80% (w/w) dimethylacetamide and 20% (w/w) pentane. Another 2hour bake at 50° C. was performed to remove the solvent.

A select number of stents were analyzed to quantify the coatingcomponents. For the primer layer, there was a target dry weight of 40 μgof polymer, and a measured average dry weight of 45±1 μg of polymer. Forthe reservoir layer, the drug:polymer ratio was 1:1, and the measuredaverage drug content was 151 μg as determined by Example 2. For thebarrier layer, the measured average dry weight was 234 μg.

After the coatings were formed on the stents, a select number of stentswere tested for the drug release rate from the coatings according to theprocedure described in Example 18. It was determined that the averagedrug released in 24 hours was 32.6 μg, or 21.6% of the total.

Example 20

13 mm PENTA stents were coated by spraying a 2% (w/w) solution of EVALand 98% (w/w) dimethylacetamide. The solvent was removed by baking at140° C. for 2 hours. A solution of EVAL and40-O-(2-hydroxy)ethyl-rapamycin in a mixture of 70% (w/w)dimethylacetamide and 30% (w/w) ethanol was spray coated onto thestents. The stents were then baked at 50° C. for 2 hours. A barrierlayer was formed by spraying the stents with a solution of EVAL in amixture of 80% (w/w) dimethylacetamide and 20% (w/w) pentane. Another 2hour bake at 50° C. was performed to remove the solvent.

A select number of stents were analyzed to quantify the coatingcomponents. For the primer layer, there was a target dry weight of 40 μgof polymer, and a measured average dry weight of 44±3 μg of polymer. Forthe reservoir layer, the drug:polymer ratio was 1:1.8, and the measuredaverage drug content was 97 μg as determined by Example 2. For thebarrier layer, the measured average dry weight was 184 μg.

After the coatings were formed on the stents, a select number of stentswere tested for the drug release rate from the coatings according to theprocedure described in Example 18. It was determined that the averagedrug released in 24 hours was 24.1 μg, or 24.8% of the total.

Example 21

13 mm PENTA stents were coated by spraying a 2% (w/w) solution of EVALand 98% (w/w) dimethylacetamide. The solvent was removed by baking at140° C. for 2 hours. A solution of EVAL and40-O-(2-hydroxy)ethyl-rapamycin in a mixture of 70% (w/w)dimethylacetamide and 30% (w/w) ethanol was spray coated onto thestents. The stents were then baked at 50° C. for 2 hours. A barrierlayer was formed by spraying the stents with a solution of EVAL in amixture of 80% (w/w) dimethylacetamide and 20% (w/w) pentane. Another 2hour bake at 50° C. was performed to remove the solvent.

A select number of stents were analyzed to quantify the coatingcomponents. For the primer layer, there was a target dry weight of 40 μgof polymer, and a measured average dry weight of 41±1 μg of polymer. Forthe reservoir layer, the drug:polymer ratio was 1:1.8, and the measuredaverage drug content was 227 μg as determined by Example 2. For thebarrier layer, the measured average dry weight was 181 μg.

After the coatings were formed on the stents, a select number of stentswere tested for the drug release rate from the coatings according to theprocedure described in Example 18. It was determined that the averagedrug released in 24 hours was 27.5 μg, or 12.1% of the total.

Example 22

13 mm PENTA stents were coated by spraying a 2% (w/w) solution of EVALand 98% (w/w) dimethylacetamide. The solvent was removed by baking at140° C. for 2 hours. A solution of EVAL and40-O-(2-hydroxy)ethyl-rapamycin in a mixture of 70% (w/w)dimethylacetamide and 30% (w/w) ethanol was spray coated onto thestents. The stents were then baked at 50° C. for 2 hours. No barrierlayer was applied for this Example.

A select number of stents were analyzed to quantify the coatingcomponents. For the primer layer, there was a target dry weight of 40 μgof polymer, and a measured average dry weight of 44±2 μg of polymer. Forthe reservoir layer, the drug:polymer ratio was 1:1.8, and the measuredaverage drug content was 221 μg as determined by Example 2.

After the coatings were formed on the stents, a select number of stentswere tested for the drug release rate from the coatings according to theprocedure described in Example 18. It was determined that the averagedrug released in 24 hours was 129.4 μg, or 58.55% of the total.

Example 23

13 mm PENTA stents were coated by spraying a 2% (w/w) solution of EVALand 98% (w/w) dimethylacetamide. The solvent was removed by baking at140° C. for 2 hours. A solution of EVAL and40-O-(2-hydroxy)ethyl-rapamycin in a mixture of 70% (w/w)dimethylacetamide and 30% (w/w) ethanol was spray coated onto thestents. The stents were then baked at 50°0 C. for 2 hours. A barrierlayer was formed by spraying the stents with a solution of EVAL in amixture of 80% (w/w) dimethylacetamide and 20% (w/w) pentane. Another 2hour bake at 50° C. was performed to remove the solvent.

A select number of stents were analyzed to quantify the coatingcomponents. For the primer layer, there was a target dry weight of 40 μgof polymer, and a measured average dry weight of 42 μg of polymer. Forthe reservoir layer, the drug:polymer ratio was 1:1.5, and the measuredaverage drug content was 184 μg as determined by Example 2. For thebarrier layer, the measured average dry weight was 81 μg.

After the coatings were formed on the stents, a select number of stentswere tested for the drug release rate from the coatings according to theprocedure described in Example 18. It was determined that the averagedrag released in 24 hours was 70.1 μg, or 38.1% of the total.

Example 24

8 mm PIXEL stents were coated by spraying a 2% (w/w) solution of EVALand 98% (w/w) dimethylacetamide. The solvent was removed by baking at140° C. for 2 hours. A solution of EVAL and40-O-(2-hydroxy)ethyl-rapamycin in a mixture of 70% (w/w)dimethylacetamide and 30% (w/w) ethanol was spray coated onto thestents. The stents were then baked at 50° C. for 2 hours. A barrierlayer was formed by spraying the stents with a solution of EVAL in amixture of 80% (w/w) dimethylacetamide and 20% (w/w) pentane. Another 2hour bake at 50° C. was performed to remove the solvent.

A select number of stents were analyzed to quantify the coatingcomponents. For the primer layer, there was a target dry weight of 40 μgof polymer, and a measured average dry weight of 45±1 μg of polymer. Forthe reservoir layer, the drug:polymer ratio was 1:1.75, and the measuredaverage drug content was 200 μg as determined by Example 2. For thebarrier layer, the measured average dry weight was 180 μg.

After the coatings were formed on the stents, a select number of stentswere tested for the drug release rate from tire coatings according tothe procedure described in Example 18. It was determined that theaverage drug released in 24 hours was 39.0 μg, or 19.5% of the total.

Example 25

8 mm PIXEL stents were coated by spraying a 2% (w/w) solution of EVALand 98% (w/w) dimethylacetamide. The solvent was removed by baking at140° C. for 2 hours. A solution of EVAL and40-O-(2-hydroxy)ethyl-rapamycin in a mixture of 70% (w/w)dimethylacetamide and 30% (w/w) ethanol was spray coated onto thestents. The stents were then baked at 50° C. for 2 hours. A barrierlayer was formed by spraying the stents with a solution of EVAL in amixture of 80% (w/w) dimethylacetamide and 20% (w/w) pentane. Another 2hour bake at 50° C. was performed to remove the solvent.

A select number of stents were analyzed to quantify the coatingcomponents. For the primer layer, there was a target dry weight of 40 μgof polymer, and a measured average dry weight of 41±4 μg of polymer. Forthe reservoir layer, the drug:polymer ratio was 1:1, and the measuredaverage drug content was 167 μg as determined by Example 2. For thebarrier layer, the measured average dry weight was 184 μg.

After the coatings were formed on the stents, a select number of stentswere tested for the drug release rate from the coatings according to theprocedure described in Example 18. It was determined that the averagedrug released in 24 hours was 6.0 μg, or 3.6% of the total.

Example 26

8 mm PIXEL stents were coated by spraying a 2% (w/w) solution of EVALand 98% (w/w) dimethylacetamide. The solvent was removed by baking at140° C. for 2 hours. A solution of EVAL and40-O-(2-hydroxy)ethyl-rapamycin in a mixture of 70% (w/w)dimethylacetamide and 30% (w/w) ethanol was spray coated onto thestents. The stents were then baked at 50° C. for 2 hours. A barrierlayer was formed by spraying the stents with a solution of EVAL in amixture of 80% (w/w) dimethylacetamide and 20% (w/w) pentane. Another 2hour bake at 50° C. was performed to remove the solvent.

A select number of stents were analyzed to quantify the coatingcomponents. For the primer layer, there was a target dry weight of 26 μgof polymer, and a measured average dry weight of 24±2 μg of polymer. Forthe reservoir layer, the drug:polymer ratio was 1:1.25, and the measuredaverage drug content was 120 μg as determined by Example 2. For thebarrier layer, the measured average dry weight was 138 μg.

After the coatings were formed on the stents, a select number of stentswere tested for the drug release rate from the coatings according to theprocedure described in Example 18. It was determined that the averagedrug released in 24 hours was 11.0 μg, or 9.2% of the total.

Example 27

13 mm PENTA stents were coated by spraying a 2% (w/w) solution of EVALand 98% (w/w) dimethylacetamide. The solvent was removed by baking at140° C. for 2 hours. A solution of EVAL and40-O-(2-hydroxy)ethyl-rapamycin in a mixture of 70% (w/w)dimethylacetamide and 30% (w/w) ethanol was spray coated onto thestents. The stents were then baked at 50° C. for 2 hours. A barrierlayer was formed by spraying the stents with a solution of 1% (w/w)polybutylmethacrylate, 5.7% (w/w) acetone, 50% (w/w) xylene and 43.3%(w/w) HFE FLUX REMOVER (Techspray, Amarillo, Tex.). Another 2 hour bakeat 50° C. was performed to remove the solvent.

A select number of stents were analyzed to quantify the coatingcomponents. For the primer layer, there was a target dry weight of 40 μgof polymer, and a measured average dry weight of 44±4 μg of polymer. Forthe reservoir layer, the drug:polymer ratio was 1:1, and the measuredaverage drug content was 183 μg as determined by Example 2. For thebarrier layer, the measured average dry weight was 168 μg.

After the coatings were formed on the stents, a select number of stentswere tested for the drug release rate from the coatings according to theprocedure described in Example 18. It was determined that the averagedrug released in 24 hours was 21.6 μg, or 11.8% of the total.

Example 28

13 mm PENTA stents were coated by spraying a 2% (w/w) solution of EVALand 98% (w/w) dimethylacetamide. The solvent was removed by baking at140° C. for 2 hours. A solution of EVAL and40-O-(2-hydroxy)ethyl-rapamycin in a mixture of 70% (w/w)dimethylacetamide and 30% (w/w) ethanol was spray coated onto thestents. The stents were then baked at 50° C. for 2 hours. A barrierlayer was formed by spraying the stents with a solution of 1% (w/w)polybutylmethacrylate, 5.7% (w/w) acetone, 50% (w/w) xylene and 43.3%(w/w) HFE FLUX REMOVER. Another 2 hour bake at 50° C. was performed toremove the solvent.

A select number of stents were analyzed to quantify the coatingcomponents. For the primer layer, there was a target dry weight of 40 μgof polymer, and a measured average dry weight of 41±2 μg of polymer. Forthe reservoir layer, the drug:polymer ratio was 1:1.8, and the measuredaverage drug content was 102 μg as determined by Example 2. For thebarrier layer, the measured average dry weight was 97 μg.

After the coatings were formed on the stents, a select number of stentswere tested for the drug release rate from the coatings according to theprocedure described in Example 18. It was determined that the averagedrug released in 24 hours was 9.1 μg, or 8.9% of the total.

Example 29

8 mm PIXEL stents were coated by spraying a 2% (w/w) solution of EVALand 98% (w/w) dimethylacetamide. The solvent was removed by baking at140% for 2 hours. A solution of EVAL and 40-O-(2-hydroxy)ethyl-rapamycinin a mixture of 70% (w/w) dimethylacetamide and 30% (w/w) ethanol wasspray coated onto the stents. The stents were then baked at 50° C. for 2hours. A barrier layer was formed by spraying the stems with a solutionof 1% (w/w) polybutylmethacrylate, 5.7% (w/w) acetone, 50% (w/w) xyleneand 43.3% (w/w) HFE FLUX REMOVER (Techspray, Amarillo, Tex.). Another 2hour bake at 50° C. was performed to remove the solvent.

A select number of stents were analyzed to quantify the coatingcomponents. For the primer layer, there was a target dry weight of 26 μgof polymer, and a measured average dry weight of 27±2 μg of polymer. Forthe reservoir layer, the drug:polymer ratio was 1:1.25, and the measuredaverage drug content was 120 μg as determined by Example 2. For thebarrier layer, the measured average dry weight was 68 μg.

After the coatings were formed on the stents, a select number of stentswere tested for the drug release rate from the coatings according to theprocedure described in Example 18. It was determined that the averagedrug released in 24 hours was 22.0 μg, or 18.3% of the total.

Example 30

A select number of stents from Example 3 were tested for the drugrelease rate from the coatings according to the procedure described inExample 18. It was determined that the average drug released in 24 hourswas 22.8 μg, or 11.1% of the total.

Example 31

A select number of stents from Example 4 were tested for the drugrelease rate from the coatings according to the procedure described inExample 18. It was determined that the average drug released in 24 hourswas 57.0 μg, or 20.2% of the total.

Example 32

Two stents were coated by spraying a 2% (w/w) solution of EVAL and 98%(w/w) dimethylacetamide to form a primer layer. For the primer layer,there was a target dry weight of 100 μg of polymer, and the measured dryweights were 93 μg and 119 μg, respectively. The two stents were thencoated with an EVAL-40-O-(2-hydroxy)ethyl-rapamycin blend at adrug:polymer ratio of 2:1 to produce a reservoir layer. Alterapplication, it was determined that the reservoir layers had weights of610 μg and 590 μg, respectively. From the total weight of the reservoirlayers and the drug:polymer ratio, it was estimated that the coatingscontained about 407 μg and 393 μg of 40-O-(2-hydroxy)ethyl-rapamycin,respectively. Polymeric barrier layers were also applied to the stentsand it was determined that the weights of the barrier layers were 279 μgand 377 μg, respectfully.

The stents from this Example were then sterilized using an ethyleneoxide sterilization process. In particular, the stents were placed in achamber and exposed to ethylene oxide gas for 6 hours at 130-140° F.,with a relative humity of 45-80%. The stents were then aerated for about72 hours at 110-130° F.

After sterilization, the coatings were then analyzed using an HPLC todetermine the peak purity of the drug in the stent coatings. It wasdetermined that the 40-O-(2-hydroxy)ethyl-rapamycin in the coatings hadpeak purities of about greater than 95%. FIG. 4 is a chromatographshowing the peak purity the 40-O-(2-hydroxy)ethyl-rapamycin in one ofthe coatings, labeled “ETO,” as compared to a reference standard for40-O-(2-hydroxy)ethyl-rapamycin, labeled “Ref. Std.”

Example 33

Two stents were coated by spraying a 2% (w/w) solution of EVAL and 98%(w/w) dimethylacetamide to form a primer layer. For the primer layer,there was a target dry weight of 100 μg of polymer, and the measured dryweights were 99 μg and 94 μg, respectively. The two stents were thencoated with an EVAL-40-O-(2-hydroxy)ethyl-rapamycin blend at adrug:polymer ratio of 2:1 to produce a reservoir layer. Afterapplication, it was determined that the reservoir layers had weights of586 μg and 588 μg, respectively. From the total weight of the reservoirlayers and the drug:polymer ratio, it was estimated that the coatingscontained about 391 μg and 392 μg of 40-O-(2-hydroxy)ethyl-rapamycin,respectively. Polymeric barrier layers were also applied to the stentsand it was determined that the weights of the barrier layers were 380 μgand 369 μg, respectfully.

The stents from this Example were then sterilized using an e-beamsterilization process. In particular, the stents were placed in a stentcontainer which was run through an e-beam chamber. While moving throughthe e-beam chamber via a conveyor belt, the stent container was exposedto an e-beam with a constant energy level so that the stent containerreceived between 33.11 and 46.24 KGy. The stent therefore at any pointalong the length of the stent received at a minimum 25 KGy.

After sterilization, the coating was then analyzed using an HPLC todetermine the peak purity of the drug in the stent coating. It wasdetermined that the 40-O-(2-hydroxy)ethyl-rapamycin in the coating had apeak purity of about greater than 95%. FIG. 4 is a chromatograph showingthe peak purity the 40-O-(2-hydroxy)ethyl-rapamycin in one of thecoatings, labeled “e-beam,” as compared to a reference standard for40-O-(2-hydroxy)ethyl-rapamycin, labeled “Ref. Std.”

Example 34

13 mm PENTA stents were coated by spraying a 2% (w/w) solution of EVALand 98% (w/w) dimethylacetamide. The solvent was removed by baking at140° C. for 2 hours. A solution of EVAL and40-O-(2-hydroxy)ethyl-rapamycin in a mixture of 70% (w/w)dimethylacetamide and 30% (w/w) ethanol was spray coated onto thestents. The stents were then baked at 50° C. for 2 hours. A barrierlayer was formed by spraying the stents with a solution of EVAL in amixture of 80% (w/w) dimethylacetamide and 20% (w/w) pentane. Another 2hour bake at 50° C. was performed to remove the solvent.

A select number of stems were analyzed to quantify the coatingcomponents. For the primer layer, there was a target dry weight of 40 μgof polymer, and a measured average dry weight of 44±3 μg of polymer. Forthe reservoir layer, the drug:polymer ratio was 1:2, and the measuredaverage drug content was 245 μg as determined by Example 2. For thebarrier layer, the measured average dry weight was 104 μg.

After the coatings were formed on the stents, a select number of stentswere tested for the drug release rate from the coatings according to theprocedure described in Example 18. It was determined that the averagedrug released in 24 hours was 23.5 μg, or 9.6% of the total.

Example 35

13 mm PENTA stents were coated by spraying a 2% (w/w) solution of EVALand 98% (w/w) dimethylacetamide. The solvent was removed by baking at140° C. for 2 hours. A solution of EVAL and40-O-(2-hydroxy)ethyl-rapamycin in a mixture of 70% (w/w)dimethylacetamide and 30% (w/w) ethanol was spray coated onto thestents. The stents were then baked at 50° C. for 2 hours. A barrierlayer was formed by spraying the stents with a solution of EVAL in amixture of 80% (w/w) dimethylacetamide and 20% (w/w) pentane. Another 2hour bake at 50° C. was performed to remove the solvent.

A select number of stents were analyzed to quantify the coatingcomponents. For the primer layer, there was a target dry weight of 40 μgof polymer, and a measured average dry weight of 45±3 μg of polymer. Forthe reservoir layer, the drug:polymer ratio was 1:1.5, and the measuredaverage drug content was 337 μg as determined by Example 2. For thebarrier layer, the measured average dry weight was 169 μg.

After the coatings were formed on the stents, a select number of stentswere tested for the drug release rate from the coatings according to theprocedure described in Example 18. It was determined that the averagedrug released in 24 hours was 37.1 μg, or 11.0% of the total.

Example 36

Stents from Example 34 and stents from Example 35 were sterilizedaccording to the process described in Example 32. The released rates ofthe drug in the stent coatings of sterilized stents and non-sterilizedwere then tested according to the process described in Example 5. Theresults of the release rate test are graphically shown in FIG. 5.

Example 37

A 13 mm PENTA stent can be coated by spraying a solution of EVAL,40-O-(2-hydroxy)ethyl-rapamycin and ethanol onto the stent. The stent isthen baked at 50° C. for 2 hours to yield a reservoir coating with 300μg of EVAL and 300 μg of 40-O-(2-hydroxy)ethyl-rapamycin. A barrierlayer can be formed by spraying the stent with a solution of EVAL andpentane. A second 2 hour bake at 50° C. can be performed to remove thesolvent to yield a barrier coating with 320 μg of EVAL.

Example 38

A 13 mm PENTA stent can be coated by spraying a solution of EVAL andDMAC onto the stent. The solvent is removed by baking at 140° C. for 2hours to yield a primer coating with 100 μg of EVAL. A reservoir layercan be applied by spraying a solution of EVAL,40-O-(2-hydroxy)ethyl-rapamycin and ethanol onto the stent. The stent isthen baked at 50° C. for 2 hours to yield a reservoir coating with 200μg of EVAL and 400 μg of 40-O-(2-hydroxy)ethyl-rapamycin. A barrierlayer can be formed by spraying the stent with a solution of EVAL andpentane. A second 2 hour bake at 50° C. is performed to remove thesolvent to yield a barrier coating with 350 μg of EVAL.

Example 39

A 13 mm PENTA stent can be coated by spraying a solution of EVAL,40-O-(2-hydroxy)ethyl-rapamycin and ethanol onto the stent. The stent isthen baked at 50° C. for 2 hours to yield a reservoir coating with 500μg of EVAL and 250 μg of 40-O-(2-hydroxy)ethyl-rapamycin. A barrierlayer can be formed by spraying the stent with a solution of EVAL andpentane. A second 2 hour bake at 50° C. is performed to remove thesolvent to yield a barrier coating with 300 μg of EVAL.

Example 40

A 13 mm PENTA stent can be coated by spraying a solution of EVAL,40-O-(2-hydroxy)ethyl-rapamycin and ethanol onto the stent. The stent isthen baked at 50° C. for 2 hours to yield a reservoir coating with 475μg of EVAL and 175 μg of 40-O-(2-hydroxy)ethyl-rapamycin. A barrierlayer can be formed by spraying the stent with a solution of EVAL andpentane. A second 2 hour bake at 50° C. is performed to remove thesolvent to yield a barrier coating with 300 μg of EVAL.

Example 41

An 8 mm PIXEL stent can be coated by spraying a solution of EVAL and40-O-(2-hydroxy)ethyl-rapamycin in a mixture of dimethylacetamide andethanol onto the stent. The stent is then baked at 50° C. for 2 hours toyield a reservoir coating with 400 μg of EVAL and 200 μg of40-O-(2-hydroxy)ethyl-rapamycin. A barrier layer can be formed byspraying the stent with a solution of EVAL and a mixture ofdimethylacetamide and pentane. A second 2 hour bake at 50° C. isperformed to remove the solvent to yield a barrier coating with 300 μgof EVAL.

Example 42

An 8 mm Pixel stent can be coated by spraying a solution of EVAL and40-O-(2-hydroxy)ethyl-rapamycin in a mixture of dimethylacetamide andethanol onto the stent. The stent is then baked at 50° C. for 2 hours toyield a reservoir coating with 400 μg of EVAL and 200 μg of40-O-(2-hydroxy)ethyl-rapamycin. A barrier layer can be formed byspraying the stent with a solution of polybutylmethacrylate (“PBMA”) andHFE FLUX REMOVER. A second 2 hour bake at 50° C. is performed to removethe solvent to yield a barrier coating with 150 μg of PBMA.

Example 43

An 8 mm PIXEL stent can be coated by spraying a solution of EVAL and40-O-(2-hydroxy)ethyl-rapamycin in a mixture of dimethylacetamide andethanol onto the stent. The stent is then baked at 50° C. for 2 hours toyield a reservoir coating with 200 μg of EVAL and 200 μg of40-O-(2-hydroxy)ethyl-rapamycin. A barrier layer can be formed byspraying the stent with a solution of EVAL and a mixture ofdimethylacetamide and pentane. A second 2 hour bake at 50° C. isperformed to remove the solvent to yield a barrier coating with 200 μgof EVAL.

Example 44

An 8 mm PIXEL stent can be coated by spraying a solution of EVAL and40-O-(2-hydroxy)ethyl-rapamycin in a mixture of dimethylacetamide andethanol onto the stent. The stent is then baked at 50° C. for 2 hours toyield a reservoir coating with 200 μg of EVAL and 200 μg of40-O-(2-hydroxy)ethyl-rapamycin. A barrier layer can formed by sprayingthe stent with a solution of PBMA and HFE FLUX REMOVER. A second 2 hourbake at 50° C. is performed to remove the solvent to yield a barriercoating with 150 μg of PBMA.

Example 45

An 8 mm PIXEL stent can be coated by spraying a solution of EVAL and40-O-(2-hydroxy)ethyl-rapamycin in a mixture of dimethylacetamide andethanol onto the stent. The stent is then baked at 50° C. for 2 hours toyield a reservoir coating with 200 μg of EVAL and 200 μg of40-O-(2-hydroxy)ethyl-rapamycin. A barrier layer can be formed byspraying the stent with a solution of EVAL and a mixture ofdimethylacetamide and pentane. A second 2 hour bake at 50° C. isperformed to remove the solvent to yield a barrier coating with 200 μgof EVAL.

Example 46

An 8 mm PIXEL stent can be coated by spraying a solution of EVAL and40-O-(2-hydroxy)ethyl-rapamycin in a mixture of dimethylacetamide andethanol onto the stent. The stent is then baked at 50° C. for 2 hours toyield a reservoir coating with 200 μg of EVAL and 200 μg of40-O-(2-hydroxy)ethyl-rapamycin. A barrier layer can be formed byspraying the stent with a solution of PBMA and HFE FLUX REMOVER. Asecond 2 hour bake at 50° C. is performed to remove the solvent to yielda barrier coating with 100 μg of PBMA.

Example 47

An 8 mm PIXEL stent can be coated by spraying a solution of EVAL and40-O-2-hydroxy)ethyl-rapamycin in a mixture of dimethylacetamide andethanol onto the stent. The stent is then baked at 50° C. for 2 hours toyield a reservoir coating with 270 μg of EVAL and 150 μg of40-O-(2-hydroxy)ethyl-rapamycin. A barrier layer can be formed byspraying the stent with a solution of EVAL and a mixture ofdimethylacetamide and pentane. A second 2 hour bake at 50° C. isperformed to remove the solvent to yield a barrier coating with 150 μgof EVAL.

Example 48

An 8 mm PIXEL stent can be coated by spraying a solution of EVAL and40-O-(2-hydroxy)ethyl-rapamycin in a mixture of dimethylacetamide andethanol onto the stent. The stent is then baked at 50° C. for 2 hours toyield a reservoir coating with 170 μg of EVAL and 150 μg of40-O-(2-hydroxy)ethyl-rapamycin. A barrier layer can be formed byspraying the stent with a solution of PBMA and HFE FLUX REMOVER. Asecond 2 hour bake at 50° C. is performed to remove the solvent to yielda barrier coating with 75 μg of PBMA.

Example 49

An 8 mm PIXEL stent can be coated by spraying a solution of EVAL and40-O-(2-hydroxy)ethyl-rapamycin in a mixture of dimethylacetamide andethanol onto the stent. The stent is then baked at 50° C. for 2 hours toyield a reservoir coating with 150 μg of EVAL and 150 μg of40-O-(2-hydroxy)ethyl-rapamycin. A barrier layer can be formed byspraying the stent with a solution of EVAL and a mixture ofdimethylacetamide and pentane. A second 2 hour bake at 50° C. isperformed to remove the solvent to yield a barrier coating with 200 μgof EVAL. A finishing layer can then applied by spraying the stent with asolution of EVAL, polyethyleneoxide (molecular weight of 17.5 K) (“PEO”)and dimethylacetamide. The stent is baked at 50° C. for 2 hours toremove the solvent to yield a finishing coating with 83 μg of EVAL and17 μg of PEO.

Example 50

An 8 mm PIXEL stent can be coated by spraying a solution of EVAL and40-O-(2-hydroxy)ethyl-rapamycin in a mixture of dimethylacetamide andethanol onto the stent. The stent is then baked at 50° C. for 2 hours toyield a reservoir coating with 270 μg of EVAL and 150 μg of40-O-(2-hydroxy)ethyl-rapamycin. A barrier layer can formed by sprayingthe stent with a solution of EVAL and a mixture of dimethylacetamide andpentane. A second 2 hour bake at 50° C. is performed to remove thesolvent to yield a barrier coating with 150 μg of EVAL. A finishinglayer can then applied by spraying the stem with a solution of EVAL, PEOand dimethylacetamide. The stent is baked at 50° C. for 2 hours toremove the solvent to yield a finishing coating with 83 μg of EVAL and17 μg of PEO.

Example 51

An 8 mm PIXEL stent can be coated by spraying a solution of EVAL and40-O-(2-hydroxy)ethyl-rapamycin in a mixture of dimethylacetamide andethanol onto the stent. The stent is then baked at 50° C. for 2 hours toyield a reservoir coating with 200 μg of EVAL and 200 μg of40-O-(2-hydroxy)ethyl-rapamycin. A barrier layer can be formed byspraying the stent with a solution of EVAL and a mixture ofdimethylacetamide and pentane. A second 2 hour bake at 50° C. isperformed to remove the solvent to yield a barrier coating with 100 μgof EVAL.

Example 52

An 8 mm PIXEL stent can be coated by spraying a solution of EVAL and40-O-(2-hydroxy)ethyl-rapamycin in a mixture of dimethylacetamide andethanol onto the stent. The stent is then baked at 50° C. for 2 hours toyield a reservoir coating with 200 μg of EVAL and 200 μg of40-O-(2-hydroxy)ethyl-rapamycin. A barrier layer can be formed byspraying the stent with a solution of EVAL, KYNAR and HFE FLUX REMOVER.A second 2 hour bake at 50° C. is performed to remove the solvent toyield a barrier coating with 50 μg of EVAL and 50 μg of KYNAR.

Example 53

An 8 mm PIXEL stent can be coated by spraying a solution of EVAL and40-O-(2-hydroxy)ethyl-rapamycin in a mixture of dimethylacetamide andethanol onto the stent. The stent is then baked at 50° C. for 2 hours toyield a reservoir coating with 350 μg of EVAL and 200 μg of40-O-(2-hydroxy)ethyl-rapamycin. A barrier layer is formed by sprayingthe stent with a solution of EVAL and a mixture of dimethylacetamide andpentane. A second 2 hour bake at 50° C. is performed to remove thesolvent to yield a barrier coating with 200 μg of EVAL.

Example 54

An 8 mm PIXEL stent can be coated by spraying a solution of EVAL and40-O-(2-hydroxy)ethyl-rapamycin in a mixture of dimethylacetamide andethanol onto the stent. The stent is then baked at 50° C. for 2 hours toyield a reservoir coating with 350 μg of EVAL and 200 μg of40-O-(2-hydroxy)ethyl-rapamycin. A barrier layer can be formed byspraying the stent with a solution of PBMA and HFE FLUX REMOVER. Asecond 2 hour bake at 50° C. is performed to remove the solvent to yielda barrier coating with 100 μg of PBMA.

Example 55

An 8 mm PIXEL stent can be coated by spraying a solution of EVAL and40-O-(2-hydroxy)ethyl-rapamycin in a mixture of dimethylacetamide andethanol onto the stent. The stent is then baked at 50° C. for 2 hours toyield a reservoir coating with 350 μg of EVAL and 200 μg of40-O-(2-hydroxy)ethyl-rapamycin. A barrier layer can be formed byspraying the stent with a solution of EVAL and a mixture ofdimethylacetamide and pentane. A second 2 hour bake at 50° C. isperformed to remove the solvent to yield a barrier coating with 200 μgof EVAL.

Example 56

An 8 mm PIXEL stent is coated by spraying a solution of EVAL and40-O-(2-hydroxy)ethyl-rapamycin in a mixture of dimethylacetamide andethanol onto the stent. The stent is then baked at 50° C. for 2 hours toyield a reservoir coating with 350 μg of EVAL and 200 μg of40-O-(2-hydroxy)ethyl-rapamycin. A barrier layer can be formed byspraying the stent with a solution of EVAL and a mixture ofdimethylacetamide and pentane. A second 2 hour bake at 50° C. isperformed to remove the solvent to yield a barrier coating with 100 μgof EVAL. A finishing layer can then be applied by spraying the stentwith a solution of EVAL, PEO and dimethylacetamide. The stent is bakedat 50° C. for 2 hours to remove the solvent to yield a finishing coatingwith 83 μg of EVAL and 17 μg of PEO.

Example 57

An 8 mm PIXEL stent can be coated by spraying a solution of EVAL and40-O-(2-hydroxy)ethyl-rapamycin in a mixture of dimethylacetamide andethanol onto the stent. The stent is then baked at 50° C. for 2 hours toyield a reservoir coating with 350 μg of EVAL and 200 μg of40-O-(2-hydroxy)ethyl-rapamycin. A barrier layer can be formed byspraying the stent with a solution of PBMA and HFE FLUX REMOVER. Asecond 2 hour bake at 50° C. is performed to remove the solvent to yielda barrier coating with 75 μg of PBMA. A finishing layer can then beapplied by spraying the stent with a solution of PBMA, PEO anddimethylacetamide. The stent is baked at 50° C. for 2 hours to removethe solvent to yield a finishing coating with 62.5 μg of PBMA and 12.5μg of PEO.

While particular embodiments of the present invention have been shownand described, it will be obvious to those skilled in the art thatchanges and modifications can be made without departing from thisinvention in its broader aspects.

What is claimed is:
 1. A stent comprising a radially expandable body anda coating covering at least a portion of the body, the coatingcontaining 40-O-(2-hydroxy)ethyl-rapamycin, or an analog or derivativethereof, wherein the release rate of the40-O-(2-hydroxy)ethyl-rapamycin, or the analog or derivative thereof, in24 hours after the implantation of the stent is less than about 50% ofthe total amount contained in the coating.
 2. The stent of claim 1,wherein the derivative or analogue of 40-O-(2-hydroxy)ethyl-rapamycinincludes 40-O-(3-hydroxy)propyl-rapamycin and40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin.
 3. The stent of claim 1,wherein the coating comprises an ethylene vinyl alcohol copolymer. 4.The stent of claim 1, wherein the coating is made from a polymerincluding a first region having a first degree of crystallinity and asecond region having a second degree of crystallinity, the second degreeof crystallinity being greater than the first degree of crystallinity.5. The stent of claim 4, wherein the second region is positioned beneaththe first region.